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ISCCM

TM

Manual of
RRT and ECMO in ICU
A Reference Book for Practicing Intensivists
Editor
Rajesh Chandra Mishra
MBBS MD (Medicine) FNB EDIC FCCM FCCP FICP
Consultant Intensivist and Internist
General Secretary ISCCM 2019-20
Ahmedabad, Gujarat, India

Co-Editors
Kanwalpreet Sodhi
DA DNB IDCCM
European Diploma in Intensive Care (EDIC)
Section Editor, Journal Anesthesiology Clinical Pharmacology (JOACP)
Director and Head, Department of Critical Care
Deep Hospital, Ludhiana, Punjab, India
KC Prakash Poonam Malhotra Kapoor
MD DNB (Nephrology) MD DNB MNAMS FIACTA (Hony)
FTEE (Hony) FISCU (Hony)
Senior Consultant Nephrologist
Professor, Department of Cardiac Anesthesiology
Department of Nephrology
Cardiothoracic Center, All India Institute of Medical
Apollo Hospitals, Chennai
Sciences (AIIMS), New Delhi, India
Coordinator of Dialysis Satellite Centers
Editor-In-Chief, Journal of Cardiac Critical Care
Apollo Dialysis Clinic
President, IACTA
Chennai, Tamil Nadu, India
President, SCA-Delhi and NCR Branch
Past secretary of PDSI
Past President, ECMO Society of India
Past Editor of IJPD
Secretary and Chairman, Academics – The
Simulation Society (TSS)

Foreword
Subhal Bhalchandra Dixit

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ISCCM Manual of RRT and ECMO in ICU: A Reference Book for Practicing Intensivists
First Edition: 2020
ISBN: 978-93-89587-99-9
Dedication
Dedicated to Indian Society of Critical Care Medicine (ISCCM)
Contributors

Abdul Samad Ansari MD FNB IDCCM Anvesh Golla MBBS MD DM


Director, Critical Care Services Senior Resident
Department of Critical Care Department of Nephrology
Heart Institute, Balabhai Nanavati Hospital Nizams Institute of Medical Sciences
Mumbai, Maharashtra, India Hyderabad, Telangana, India

Ajay Padmanaban MD (Anesthesia) IDCCM


Ashish Nandwani MD DNB (Nephrology) FASN
Consultant
Senior Consultant
Department of Critical Care Medicine
Medanta Kidney and Urology Institute
Apollo Hospital
Medanta—The Medicity
Chennai, Tamil Nadu, India
Gurugram, Haryana, India
Ajith Kumar AK MBBS MD DNB EDIC FICCM
Senior Consultant and Head Babu Abraham MD (Internal Medicine) MRCP (UK)
Department of Critical Care Medicine Fellowship in Critical Care Medicine (University of Toronto)
IFCCM
Manipal Hospitals
Senior Consultant
Bengaluru, Karnataka, India
Department of Critical Care Medicine
Amrish Patel MBBS Apollo Hospital
Consultant Chennai, Tamil Nadu, India
Pulmonologist and Critical Care Specialist
Sterling Hospital Bhanu P Zawar MD
Ahmedabad, Gujarat, India Senior Consultant, Institute of Critical
Care and Anesthesia
Anand Raghunathan MBBS DA DNB FNB-Cardiac Medanta —The Medicity
(Anesthesia) FRCA-UK FCAI-Ireland EDAIC (European Board) Gurugram, Haryana, India
MFICM (Intensive Care, UK) Fellowship (Cardiac Anesthesia,
Canada)
Head, Cardiac Anesthesia Buddhika PJ Samaranayaka Bsc Msc (Clinical
Department of Cardiac Anesthesia Sciences)
Durdans Hospital Senior Perfusionist, Cardiac Surgery
Colombo, Sri Lanka Durdans Hospital
Colombo, Sri Lanka
Anil Sachdev DCH MD FICCM
Director, Division of Pediatric Emergency Chandreshkumar Sudani MBBS DNB IDCCM
Critical Care and Pulmonology Consultant, Critical Care
Institute of Child Health Medicover Hospital
Sir Ganga Ram Hospital Hyderabad, Telangana, India
New Delhi, India

Anju Grewal MBBS MD Charudatt Vaity MD EDIC


Professor, Department of Anesthesiology Senior Consultant Critical Care
Dayanand Medical College and Hospital Department of Critical Care
Ludhiana, Punjab, India Fortis Hospital, Mumbai, Maharashtra, India
viii ISCCM Manual of RRT and ECMO in ICU

Deo Shankar Patel DA IDCCM GS Wander MBBS MD


Consultant and Head Critical Care Professor and Head of Cardiology
Nayati Hospital Hero DMC Heart Institute
Agra, Uttar Pradesh, India Dayanand Medical College and Hospital
Ludhiana, Punjab, India
Past President, API
Dinesh Garg MBBS MD PDCC
Consultant Gunjan Chanchalani MD FNBE IFCCM EDIC
Cardiac Anesthesia and Critical Care Chief Intensivist,
Hero DMC Heart Institute, Dayanand Medical Department of Critical Care Medicine
College Bhatia Hospital
Ludhiana, Punjab, India Mumbai, Maharashtra, India

Dipak Viradia MBBS MD DNB Medicine Haresh Vastarpara MBBS DA IDCCM


Consultant Intensivist Consultant Intensivist
Unique Hopsital Unique Hospital
Surat, Gujarat, India Surat, Gujarat, India

Jitendra Chaudhari MD FNB EDIC


Diptimala Aggarwal DA DNB FCCM
Consultant Critical Care
Head, Department of Anesthesia and Critical Care Department of Critical Care
Pushpanjali Hospital Fortis Hospital, Mumbai, Maharashtra, India
Agra, Uttar Pradesh, India
Joyita Bharati MBBS
Ganshyam Jagathkar MBBS MD FNB FICCM Research Associate
Director, Critical Care Department of Nephrology
Medicover Hospital Postgraduate Institute of Medical Education and
Hyderabad, Telangana, India Research
Chandigarh, India

Garima Bhag MBBS MD Jyothsna Guttikonda MD


Associate Consultant Consultant and Head
Pediatric Cardiac Anesthesia and Intensive Care Department of Nephrology
Children’s Heart Center Star Hospital, Hyderabad, Telangana, India
Kokilaben Ambani Hospital
Mumbai, Maharashtra, India Kamlesh Tailor MD (Anesthesia) FNB (Cardiovascular
and Thoracic Anesthesia)
Consultant and Chief, Pediatric Cardiac Anesthesia
Girish V Kumthekar MD DNB (Nephrology)
and Intensive Care
Consultant Nephrologist
Children’s Heart Center, Kokilaben Dhirubhai
Department of Nephrology
Ambani Hospital
RENOWN Clinical Services and Star Hospital
Mumbai, Maharashtra, India
Hyderabad, Telangana, India
Kanav Anand MBBS MD Pediatrics (Gold Medalist) FPN
Gopal Raval MBBS DNB (RESP MED) DTCD EDARM Consultant, Division of Pediatric Nephrology and
MNAMS IBSM FSM Renal Transplantation
Consultant Critical Care Specialist and Department of Pediatrics
Pulmonologist Institute of Child Health
Department of Critical Care Medicine Sir Ganga Ram Hospital
Sterling Hospital, Ahmedabad, Gujarat, India New Delhi, India
Contributors ix
Kanwalpreet Sodhi DA DNB IDCCM Manender Kumar MBBS MD PDCC
European Diploma in Intensive Care (EDIC) Consultant, Cardiac Anesthesia and Critical Care
Section Editor, Journal Anesthesiology Clinical Hero DMC Heart Institute
Pharmacology (JOACP) Dayanand Medical College, Ludhiana, Punjab, India
Director and Head, Department of Critical Care
Deep Hospital, Ludhiana, Punjab, India Mansi Dandnaik MD IDCCM EDICM
Consultant Intensivist
KC Prakash MD DNB (Nephrology)
Critical Care Medicine, Sterling Hospital
Senior Consultant Nephrologist
Ahmedabad, Gujarat, India
Department of Nephrology
Apollo Hospitals, Chennai, Tamil Nadu, India
Manvi Narang MBBS PGPHM
Kesava Dev MBBS MS MCh (Cardiothoracic Surgery) Chief Operating Officer
Head, Department of Cardiac Surgery Medical Administration
Durdans Hospital Deep Hospital, Ludhiana, Punjab, India
Colombo, Sri Lanka

Khalid Ismail Khatib MD FICCM FICP


Mayur S Shah MD FNB Trainee

Professor, Department of Medicine Junior Consultant


Smt Kashibai Navale Medical College Department of Critical Care
Pune, Maharashtra, India Balabhai Nanavati Hospital
Mumbai, Maharashtra, India
Khushbu Vaghasiya MD IDCCM
Consultant Intensivist Munish Chauhan MBBS MD
Unique Hospital Consultant
Surat, Gujarat, India Critical Care Medicine
Fortis Memorial Institute
KS Nayak MD DNB FISN FISOT FASN FRCP
Gurugram, Haryana, India
Senior Nephrologist
Virinchi Hospital
Hyderabad, Telangana, India Muralidhar Kanchi MD FIACTA FICA MBA FASE
Director (Academic)
Lata Bhattacharya MD Senior Consultant and Professor
Reader Anesthesia and Intensive Care
Department of Anesthesia Narayana Hrudayalaya Hospitals
JLN Cancer Hospital Bengaluru, Karnataka, India
Bhopal, Madhya Pradesh, India

Leena Bhangale MBBS DA CTCCM


Nandhakishore Jampala MBBS DA IDCCM EDIC
Consultant, Department of Critical Care
Consultant Intensivist
Medicover Hospital
Department of Critical Care
Hyderabad, Telangana, India
Medicover Hospitals
Nasik, Maharashtra, India
Nilesh Bohra MBBS MD
Madhur Arora MBBS MD Associate Consultant
Associate Consultant Pediatric Cardiac Anesthesia and Intensive Care
Critical Care Medicine Children’s Heart Centre
Fortis Memorial Institute Kokilaben Ambani Hospital
Gurugram, Haryana, India Mumbai, Maharashtra, India
x ISCCM Manual of RRT and ECMO in ICU

Niraj Tyagi MBBS EDIC Praveen K Etta MD DM (Nephrology)


Consultant Nephrologist
Institute of Critical Care and Emergency Medicine Department of Nephrology
Sir Ganga Ram Hospital, New Delhi, India Virinchi Hospital
Hyderabad, Telangana, India
Nita George
MD Anesthesia FRCA EDIC CCT Anesthesia (UK)
Senior Consultant Priyanka H Chhabra MBBS MD DNB
Intensivist and Anesthesiologist Assistant Professor
VPS Lakeshore Hospital and Research Center Anesthesiology and Critical Care
Department of Anesthesia and Critical Care Vardhaman Mahavir Medical College and
Kochi, Kerala, India Safdarjung Hospital
New Delhi, India
Parshotam Lal Gautam MD DNB FICCM
Professor and Head
Rahul Pandit MD FJFCM FCICM FCCP EDIC IFCCM DA
Critical Care Medicine
Director, Department of Critical Care
Dayanand Medical College and Hospital
Fortis Hospital
Ludhiana, Punjab, India
Mumbai, Maharashtra, India
Poonam Malhotra Kapoor MBBS MD DNB MNAMS
FIACTA FTEE FICCC FIECMO
Raja Ramachandran MBBS MD
Professor
Assistant Professor
Department of Cardiac Anesthesiology
Department of Nephrology
Cardiothoracic Center
Postgraduate Institute of Medical Education
All India Institute of Medical Sciences (AIIMS)
and Research
New Delhi, India
Chandigarh, India
Editor, Journal of Cardiac Critical Care (JCCC)
President, IACTA; President, SCA-Delhi and NCR
Branch; Past President, ECMO Society of India Rajan Isaac MD (Medicine) DM (Nephrology)
Secretary and Chairman, Academics – The Associate Professor
Simulation Society (TSS) Department of Nephrology
Christian Medical College and Hospital
Pradip Kumar Bhattacharya MD FICCM FCCCM ACME Consultant Nephrologist
Professor and Head/Incharge Deep Hospital, Deep Kidney Care Center
Critical Care/Trauma and Emergency Ludhiana, Punjab, India
Rajendra Institute of Medical Sciences
Ranchi, Jharkhand, India
Rajasekara Chakravarthi M MD DNB (Nephrology)
Prakash Jiandani MD Consultant, Department of Nephrology
Senior Consultant Star Hospital
Department of Critical Care Director, RENOWN Clinical Services
Lilavati Hospital and Research Center Hyderabad, Telangana, India
Mumbai, Maharashtra, India

Pratheema Ramachandran DNB IDCCM IFCCM EDIC Rajesh Chandra Mishra MBBS MD (Medicine) FNB
Consultant Intensivist EDIC FCCM FCCP FICP
Department of Critical Care Medicine Consultant Intensivist and Internist
Apollo Specialty Hospitals General Secretary ISCCM 2019-20
Chennai, Tamil Nadu, India Ahmedabad, Gujarat, India
Contributors xi
Rajeev Gupta MSc (Perfusion) Ruchira Khasne MBBS DA DNB IDCCM EDAIC EDAIC
Perfusionist, Department of Cardiothoracic and Consultant and Head
Vascular Surgery Department of Critical Care Medicine
Cardiothoracic Center Ashoka-Medicover Hospital
All India Institute of Medical Sciences Nashik, Maharashtra, India
New Delhi, India
S Antony BSc
Rajyalakshmi B DA IDCCM EDIC Chief Clinical Coordinator (PD)
Consultant, Department of Critical Care Department of Nephrology
Virinchi Hospital Virinchi Hospital
Hyderabad, Telangana, India Hyderabad, Telangana, India

Ramesh Venkataraman AB (Internal Medicine) AB S Balasubramanian MD DNB


(Critical Care Medicine) FCCM FICCM Consultant Nephrologist
Senior Consultant, Department of Critical Care Apollo Hospitals
Medicine Chennai, Tamil Nadu, India
Apollo Hospitals, Chennai, Tamil Nadu, India
Sameer Bhuwania MBBS MD (Medicine) DNB
(Nephrology) (Final year student)
Ranajit Chatterjee MBBS MRCP (Dublin) EDICM DA
(Gold Medal) Critical care
Student
Chief Medical Officer and In-Charge Intensive Care Pushpawati Singhania Research Institute
and Accident and Emergency New Delhi, India
Swami Dayanand Hospital, New Delhi, India
Samir Gami MD (Respiratory Medicine)
Head, Department of Critical care, Unique Hospital
Ravi Jain MD FNB
Consultant Intensivist and Pulmonologist
Consultant Surgical Critical Care, Nayati Medicity
ECMO Specialist
Mathura, Uttar Pradesh, India
Surat, Gujarat, India

Ravindra Ghawat MD (Anesthesia) FNB (Critical Care) Sandeep Dewan MBBS IDCC
Head, Department of Critical Care Director and Head
Jupiter Hospital Intensive and Critical Care
Thane, Maharashtra, India Fortis Memorial Research Institute
Gurugram, Haryana, India
Ritu Airan MSc (Perfusion)
Perfusionist, Department of Cardiothoracic and Sandeep Sharan MBBS MD
Vascular Surgery Senior Resident DM
Cardiothoracic Center Cardiac Anaesthesia
All India Institute of Medical Sciences CN Centre AIIMS
New Delhi, India New Delhi, India

Rohit Yadav DA IDCCM Sandesh KJ MD FNB EDIC


Consultant Surgical Critical Care Consultant, Department of Critical Care
Nayati Medicity Cloud Physician Healthcare
Mathura, Uttar Pradesh, India Bengaluru, Karnataka, India
xii ISCCM Manual of RRT and ECMO in ICU

Sanjeev Saxena MBBS MD (Medicine) Sree Bhushan Raju MD DM DNB MNAMS MBA FISN
DNB (Nephrology) FICP FASN FACP
Chairman, Nephrology and Renal transplant Professor and Head
Pushpawati Singhania Research Institute Department of Nephrology
New Delhi, India Nizams Institute of Medical Sciences
Hyderabad, Telangana, India

Sarju Ralhan MBBS MS MCh Srinivas Samavedam MD FRCP DNB FNB EDIC FICCM
Chief Cardiac Surgeon DMLE MBA
Department of Cardiovascular and Head and Medical Director
Thoracic Surgery Department of Critical Care
Hero DMC Heart Institute Virinchi Hospital, Hyderabad, Telangana, India
Dayanand Medical College
Ludhiana, Punjab, India Srinivasan Ramananthan MD (Internal Medicine)
IDCCM
Consultant, Department of Critical Care
Shashank MR MD FNB Trainee
Lilavati Hospital and Medical Research Center
Resident
Mumbai, Maharashtra, India
Department of Critical Care
Balabhai Nanavati Hospital Subba Reddy K
Mumbai, Maharashtra, India MD (Anesthesiology) IDCCM IFCCM EDIC PDCC
Senior Consultant and Coordinator
Critical Care Medicine, Apollo Health City
Shikha Gupta MD (Anesthesia)
Hyderabad, Telangana, India
Professor, Department of Anesthesia
Dayanand Medical College and Hospital Subhal Bhalchandra Dixit MD IDCCM FICCM FICP
Ludhiana, Punjab, India FCCM
Consultant Critical Care and Director ICU
Simant Jha DA DNB PGDHM PDCR FIPM Sanjeevan and MJM Hospitals
ATLS Instructor Pune, Maharashtra, India
FCCS Course Director
Sumati Verma MBBS MD IFPCCM
FCCS OBS Instructor
Junior Consultant
Senior Consultant, Critical Care
Pediatric Intensive Care
Pushpawati Singhania Research Institute
Dayanand Medical College and Hospital
New Delhi, India
Ludhiana, Punjab, India

Snehal Gaikwad MBBS MD (Medicine) DNB Suneet Kathuria MD (Anesthesia)


(Nephrology) Professor, Department of Anesthesia
Consultant Nephrologist Dayanand Medical College
KEM Hospital, Pune, Maharashtra, India Ludhiana, Punjab, India

Sunil Karanth MBBS MD FNB EDIC FCICM (Aus/NZ)


Sonu Manuel MBBS MD DNB Chairman, Critical Care Medicine
Senior Resident Manipal Health Enterprises (P) Ltd
Department of Nephrology Senior Consultant
Nizams Institute of Medical Sciences Department of Critical Care Medicine
Hyderabad, Telangana, India Manipal Hospital, Bengaluru, Karnataka, India
Contributors xiii
Sunitha Binu Varghese DNB (Medicine) IDCCM EDIC Vinod Kumar Singh MD (Resp Med) EDIC FCCP FRCP
Head, Department of Critical Care (Edin) FICCM
Niramaya Hospital, Pune, Maharashtra, India Senior Consultant and Academic Coordinator
Institute of Critical Care and Emergency Medicine
SV Subhramanyam MD MISN Sir Ganga Ram Hospital
Nephrologist New Delhi, India
Department of Nephrology
Virinchi Hospital Vishwa Bharatkumar Patel MBBS
Hyderabad, Telangana, India Medical Officer
Shaleen Healthcare Ltd
Topoti Mukherjee MD (Medicine) DNB (Nephrology) Ahmedabad, Gujarat, India
Fellowship in Transplantation (Canada)
Consultant Nephrologist and Transplant Physician Vivek Gupta MBBS DNB
Manipal Hospitals Consultant
Bengaluru, Karnataka, India Cardiac Anesthesia and Intensive Care
Hero DMC Heart Institute
Tushar Patel MBBS Ludhiana, Punjab, India
Senior Consultant
Department of Pulmonology Vivekanand Jha MD DM FRCP FAMS
Sterling Hospital Executive Director
Ahmedabad, Gujarat, India The George Institute for Global Health, India
Professor of Nephrology and James Martin Fellow
Vaishali Solao MD FNB University of Oxford
Director, Intensive Care Conjoint Professor of Medicine
Jupiter Hospital University of New South Wales, Sydney, Australia
Pune, Maharashtra, India President, International Society of Nephrology

Vijay Kher MD DM (Nephrology) FAMS FRCPE Yash Javeri DA IDCCM FICCM


Chairman Head, Surgical Critical Care
Medanta Kidney and Urology Institute Nayati Medicity, Mathura
Medanta—The Medicity Chairman-SCCM Delhi NCR
Gurugram, Haryana, India Convener-Indian Sepsis Forum
Mathura, Uttar Pradesh, India
Vilesh Valsalan Kalthoonical
DNB (Medicine) DNB (Nephrology) Yatin Mehta MD MNAMS FRCA FAMS
Associate Consultant Nephrologist Chairman
Department of Nephrology Institute of Critical Care Anesthesiology
VPS Lakeshore Hospital and Research Center Medanta —The Medicity
Kochi, Kerala, India Gurugram, Haryana, India
Foreword

As, President of Indian Society of Critical Care Medicine (ISCCM), it is my proud privilege to
introduce the book titled ISCCM Manual of Renal Replacement Therapy and Extracorporeal
Membrane Oxygenation in ICU: A Reference Book for Practicing Intensivists, to the critical care
community.
With the ever-expanding field of critical care, and extracorporeal therapy being routinely
prescribed as a rescue therapy to manage critically ill patients in a variety of ICU settings, it is
the first book of its kind highlighting the theoretical and practical aspects of extracorporeal life
support (ECLS) in critical care. As an endeavor to strengthen the academics and ICU practices
across the country, the ISCCM has come up with this book to serve as a bedside reference
guide for patients undergoing ECLS.
Experts from across the country have come together through the book to share their wide
experience in the field of renal replacement therapy (RRT) and extracorporeal membrane
oxygenation (ECMO). All the contributors are renowned critical care and Nephrology experts
from leading institutions across India and overseas.
This book represents an invaluable resource for critical care professionals for the treatment
of acute kidney injury (AKI) in ICU patients, how to select and deliver the appropriate form of
RRT and ECMO, with comprehensive material accompanied by practical aspects.
The book has been divided into 2 separate sections on RRT and ECMO, comprising of 48
chapters with multiple-choice questions at the end of each section. Each chapter is dedicated to
the practical aspects of the topic elucidating practical management decision points, supported
by well-illustrated figures and tables. At the end of the chapter, there are key learning points,
which can serve as guidelines. Separate chapters for both RRT and ECMO in the pediatric
population have been included.
For the first time, a complete textbook with practical algorithms and protocols on ECLS
has been published, covering the basics as well as advances in the field of ECLS. In addition to
providing a practical resource containing the core science of ECLS principles, it is designed to
serve as (1) a companion resource to day to day RRT and ECMO management in ICU; (2) as an
educational resource for critical care students appearing for national or international exams;
and (3) an interdisciplinary document that recognizes the unique skills that each member of
the multidisciplinary team possesses and guides how to implement the ECLS program in your
ICUs. Intensivists, nephrologists, postgraduates and ICU or dialysis nurses across the country
will find this book an invaluable reference text.
I would like to congratulate Dr Rajesh C Mishra, the Chief Editor, Dr Kanwalpreet Sodhi
and team for accomplishing the difficult task successfully. I hope the book serves the purpose
for the critical care community in saving lives!
Best Wishes!!

Subhal Bhalchandra Dixit


MD IDCCM FICCM FCCM FICP
President, ISCCM 2019-2020
Preamble

The field of critical care is dynamic and ever expanding, encompassing the clinical, diagnostic
and therapeutic skills required to manage critically ill patients in diverse situation is not only
essential but mandatory. To keep pace with the developments, over the last two decades
the Indian Society of Critical Care Medicine (ISCCM) has been at the forefront of teaching
and training in intensive care. Appreciating and understanding the complexity of issues in
critical care, with minimal guidance available to intensivist across nook and corner of country,
ISCCM has come up with a book entitled, ISCCM Manual of Renal Replacement Therapy and
Extracorporeal Membrane Oxygenation in ICU: A Reference Book for Practicing Intensivists,
edited by Dr Rajesh C Mishra and colleagues.
Extracorporeal life support, routinely promoted as a ‘Rescue therapy’, though being
practiced across the ICUs in day-to-day clinical practice but still is under-explored. Combining
the knowledge and wisdom of intensivists, nephrologists, cardiac anesthetists, cardiac
surgeons and eminent physicians, the book extensively covers the practical aspects of both
renal replacement therapy (RRT) and extracorporeal membrane oxygenation (ECMO),
including non-renal uses of RRT in patients with sepsis and poisonings. The chapters are
concise, to the point, well illustrated and the layout is fresh and attractive, thus easy to read
and understand. The key points, serving as guidelines have been summarized at the end of the
chapter. Challenges in their use in children have been well highlighted, including differences
from adults. The book being clinically oriented has the potential to serve as a practical reference
book on extracorporeal therapy for practitioners of critical care. The book is a laudable effort
on the part of ISCCM and I am sure it will be well received by ICU physicians not only across
the country, but also overseas.
I am delighted to introduce the book to the critical care community and extend my best
wishes to Dr Rajesh Mishra, his coeditors and authors of the chapters.

Dhruva Chaudhry MD DNB DM (PCCM)


Senior Professor and Head
Department of Pediatric Critical Care Medicine
Dean Medical Superspecialty
Pt Bhagwat Dayal Sharma Postgraduate Institute of Medical Sciences, Rohtak
President Elect ISCCM
Preface

The ISCCM Manual of Renal Replacement Therapy and Extracorporeal Membrane Oxygenation
in ICU: A Reference Book for Practicing Intensivists is an endeavor by Indian Society of Critical
Care Medicine (ISCCM), the first book of its kind covering practical aspects of bedside
extracorporeal therapy (ECT) in ICU patients. It covers various aspects of treatment of acute
kidney injury (AKI) in ICU, selection and delivery of the appropriate form of renal replacement
therapy (RRT) and extracorporeal membrane oxygenation (ECMO), with comprehensive
material accompanied by practical aspects. The contents are focused for the young budding
intensivists and critical care students, but the book will surely be a useful bedside reference
guide for anybody handling extracorporeal therapy in critically ill patients. The chapters
are concise; discuss the techniques with diagrammatic representation, along with the
management, with key points at the end of each chapter. It covers recent indications in the
field of ECT like apheresis, ECMO for sepsis and eCPR, which may bring changes in the clinical
practice of critical care physicians. This book will also help postgraduate students and young
aspiring intensivists to prepare for various national and international examinations. It should
be an invaluable resource for critical care professionals across the country.
The book has contributions from eminent national and international critical care
physicians, nephrologists, cardiac anesthetists and cardiac surgeons, who have prepared text
based on clinical evidence, which will help readers to keep abreast with the latest knowledge
in this fast-changing medical world. The chapters are arranged with subheadings, flowcharts,
checklists and illustrations for better assimilation of content. To authenticate ECT practice in
Indian ICUs and to gain knowledge about the practices and perceptions of Indian intensivists,
we also conducted a national survey through ISCCM portal, the results of which have been
detailed as an introduction to the book.
Our special thanks to all the contributors of this book. We also thank our ISCCM friends
and position holders for their valuable inputs at all times. We enjoyed working for this book;
compiling and editing chapters. We hope the book will be informative and reader friendly.
We are thankful to M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India, for
publishing this book.

Rajesh Chandra Mishra


Kanwalpreet Sodhi
Contents

1. Introduction to Extracorporeal Life Support .......................................................... 1


Rajesh Chandra Mishra, Kanwalpreet Sodhi, Vishwa Bharatkumar Patel

Section 1 RENAL REPLACEMENT THERAPY


2. Managerial Aspects of setting up Renal Replacement Therapy in Intensive Care Unit ....... 7
Kanwalpreet Sodhi, Rajan Isaac, Manvi Narang

3. AKI in ICU: Epidemiology and Causes................................................................. 12


Sree Bhushan Raju, Anvesh Golla, Sonu Manuel

4. Types of Renal Replacement Therapy in ICU ........................................................ 19


Gopal Raval, Amrish Patel, Tushar Patel

5. Principles of Renal Replacement Therapy: Practical Applications ............................... 29


KC Prakash, S Balasubramanian

6. Indications for Renal Replacement Therapy in ICU: Renal and Nonrenal ....................... 36
Nita George, Vilesh Valsalan Kalthoonical

7. Initiation of Renal Replacement Therapy in Intensive Care Unit ................................. 39


Ashish Nandwani, Vijay Kher

8. Slow Low-efficiency Daily Dialysis in ICU ............................................................ 47


Joyita Bharati, Raja Ramachandran, Vivekanand Jha

9. Continuous Renal Replacement Therapy: Know the Machine ..................................... 56


Simant Jha, Sameer Bhuwania, Sanjeev Saxena

10. Continuous Renal Replacement Therapy Prescription in ICU ..................................... 66


Girish V Kumthekar, Jyothsna Guttikonda, Rajasekara Chakravarthi M

11. Anticoagulation in Continuous Renal Replacement Therapy ..................................... 73


Pratheema Ramachandran, Ramesh Venkataraman

12. Goals of Continuous Renal Replacement Therapy in ICU .......................................... 83


Sunitha Binu Varghese, Snehal Gaikwad
xxii ISCCM Manual of RRT and ECMO in ICU

13. Monitoring during Continuous Renal Replacement Therapy ...................................... 92


Abdul Samad Ansari, Mayur S Shah, Shashank MR

14. Switch Over from or Termination of Continuous Renal Replacement Therapy ................ 104
Ajith Kumar AK, Topoti Mukherjee

15. Continuous Renal Replacement Therapy in Specific Situations/Diseases ..................... 111


Prakash Jiandani, Gunjan Chanchalani

16. Nutrition during Renal Replacement Therapy ...................................................... 119


Khalid Ismail Khatib, Subhal Bhalchandra Dixit

17. Drug Dosing in Continuous Renal Replacement Therapy ......................................... 125


Ranajit Chatterjee, Priyanka H Chhabra

18. Troubleshooting in Renal Replacement Therapy ................................................... 140


Kanwalpreet Sodhi, Niraj Tyagi, Diptimala Aggarwal, Sumati Verma

19. Peritoneal Dialysis in Intensive Care Unit........................................................... 151


KS Nayak, SV Subhramanyam, Praveen K Etta, S Antony

20. Hemoperfusion for the Treatment of Poisoning .................................................... 157


Ganshyam Jagathkar, Nandhakishore Jampala, Chandreshkumar Sudani

21. Therapeutic Apheresis.................................................................................. 163


Vaishali Solao

22. Extracorporeal Therapies in Sepsis .................................................................. 168


Yash Javeri, Ravi Jain, Sandesh KJ

23. Renal Replacement Therapy in Children ............................................................ 180


Anil Sachdev, Kanav Anand

24. MCQs on Renal Replacement Therapy ............................................................... 190


Ravi Jain, Rohit Yadav, Yash Javeri

Section 2 EXTRACORPOREAL MEMBRANE OXYGENATION

25. Types of Extracorporeal Membrane Oxygenation: Venoarterial,


Venovenous and Hybrid Extracorporeal Membrane Oxygenation ................................. 197
Rajeev Gupta, Poonam Malhotra Kapoor

26. Physiology during Extracorporeal Membrane Oxygenation Support ............................ 212


Poonam Malhotra Kapoor, Sandeep Sharan
Contents xxiii
27. The Extracorporeal Membrane Oxygenation Team Composition ................................ 226
Srinivasan Ramananthan, Ravindra Ghawat

28. Indications of Extracorporeal Membrane Oxygenation ............................................ 231


Sandeep Dewan, Madhur Arora, Munish Chauhan

29. Know the Extracorporeal Membrane Oxygenation Machine: Circuit and Hardware........... 238
Vinod Kumar Singh

30. Cannulation, Priming and Initiation of ECMO ....................................................... 251


Manender Kumar, Sarju Ralhan, Dinesh Garg

31. Anticoagulation during Extracorporeal Membrane Oxygenation ................................. 264


Srinivas Samavedam, Rajyalakshmi B

32. Heparin and Alternatives for Anticoagulation in Extracorporeal Membrane Oxygenation ... 275
Muralidhar Kanchi

33. Monitoring during Extracorporeal Membrane Oxygenation ....................................... 282


Vivek Gupta, Rajeev Gupta, GS Wander

34. Mechanical Ventilation during Extracorporeal Membrane Oxygenation ........................ 291


Pradip Kumar Bhattacharya, Lata Bhattacharya

35. Sedation and Pain Management on Extracorporeal Membrane Oxygenation .................. 301
Babu Abraham, Ajay Padmanaban

36. Transfusion Therapy during Extracorporeal Membrane Oxygenation ........................... 308


Parshotam Lal Gautam, Suneet Kathuria, Shikha Gupta

37. Extracorporeal Membrane Oxygenation Complications ........................................... 316


Charudatt Vaity, Jitendra Chaudhari, Rahul Pandit

38. Extracorporeal Membrane Oxygenation Weaning .................................................. 324


Sandeep Dewan, Madhur Arora, Munish Chauhan

39. Extracorporeal Membrane Oxygenation Carbon Dioxide Removal .............................. 333


Ritu Airan, Poonam Malhotra Kapoor

40. Extracorporeal Cardiopulmonary Resuscitation .................................................... 342


Kanwalpreet Sodhi, Gunjan Chanchalani, Anju Grewal

41. Cardiac Issues in Extracorporeal Membrane Oxygenation........................................ 353


Bhanu P Zawar, Yatin Mehta
xxiv ISCCM Manual of RRT and ECMO in ICU

42. Extracorporeal Membrane Oxygenation for Toxicology ........................................... 360


Samir Gami, Dipak Viradia, Haresh Vastarpara, Khushbu Vaghasiya

43. Extracorporeal Membrane Oxygenation and Renal Replacement Therapy..................... 368


Anand Raghunathan, Kesava Dev, Buddhika PJ Samaranayaka

44. Nutrition in Extracorporeal Membrane Oxygenation ............................................... 385


Ruchira Khasne, Leena Bhangale, Mansi Dandnaik

45. Extracorporeal Membrane Oxygenation and Sepsis in Intensive Care Unit .................... 393
Subba Reddy K

46. Extracorporeal Membrane Oxygenator as a Bridge-to-Heart Transplant ....................... 400


Sunil Karanth

47. ECMO in Pediatric Population: Is it Different from Adults? ....................................... 406


Kamlesh Tailor, Nilesh Bohra, Garima Bhag

48. Extracorporeal Membrane Oxygenation MCQs ..................................................... 420


Sandesh KJ, Yash Javeri, Deo Shankar Patel

Index ...................................................................................................... 425


CHAPTER 1
Introduction to Extracorporeal Life Support
Rajesh Chandra Mishra, Kanwalpreet Sodhi, Vishwa Bharatkumar Patel

In recent times, critical care medicine is one of the most rapidly evolving medical specialties.
Over last two decades or so, there have been enormous advances in technology, diagnostics,
treatment, and our deeper understanding of the pathophysiology of disease processes
affecting critically ill patients. Extracorporeal life support (ECLS) is being routinely promoted
as a “rescue therapy” rather than supportive treatment for a large number of diseases in day-
to-day intensive care practice. The term “extracorporeal” literally means “outside the body”.
Extracorporeal therapy (ECT) refers to any mechanical assistance to perform physiologic
functions of the body, may be respiratory or cardiac through extracorporeal membrane
oxygenation (ECMO) or supporting kidney function through renal replacement therapy
(RRT) in different forms. ECMO is used in critically ill patients presenting as acute cardiac
and/or pulmonary dysfunctions, who are at high risk of developing acute kidney injury and
fluid overload. RRT is commonly used in ICU to provide renal replacement, electrolyte,
and fluid management. Beyond these routine indications of ECT, the therapies are further
extending their roles into toxicology and sepsis.
The use of RRT and ECMO is no longer limited to the remit of nephrologists and cardiac
surgeons, or anesthetists, respectively. They have become a routine therapy in varying
clinical conditions in intensive care unit (ICU) on daily basis. The nephrologists or dialysis
technicians are not expected to leave their dialysis units and manage ICU patients on bedside
RRT. So, an in-depth knowledge of RRT—its indications, contraindications, how and when
to begin, troubleshooting, and recent applications in non-renal conditions like poisonings,
sepsis, etc.—is mandatory for a hardcore intensivist. Similarly, ECMO is being routinely
employed for noncardiac indications in ICU patients, including acute respiratory distress
syndrome (ARDS), for extracorporeal carbon dioxide removal (ECCO2R) and for cardiac
support in poisonings like in aluminum phosphide (Celphos). So, ECMO has come out of
the cardiac surgeon’s domain and entered into the intensivists’ arena. This too mandates the
accustomization of critical care physician with the practical aspects of ECMO, its applications,
and the complications. The main incentive to launch this book dedicated to ECT is the sense
of crisis acknowledged by the society regarding the current status of RRT and ECMO in
2 ISCCM Manual of RRT and ECMO in ICU

Indian ICUs. The aim of this book is to provide concise and pragmatic practical guidelines to
clinicians managing patients on ECT in varying clinical conditions at the bedside in ICU.
To broadly assess the knowledge and practices of ECT among intensivists in Indian
ICUs, we conducted an online survey including questions on types of ICUs and the practices
of RRT and ECMO therein. A total of 320 intensivists responded to the survey through an
online portal. According to the survey, only 20% of participating Indian ICUs were closed
and 83% of open ICUs are managed by a full-timer intensivist. 94% of participating ICUs
have bedside RRT facility available. RRT in 50% ICUs is still managed by the nephrologist,
while in only 28% ICUs, RRT is intensivists’ domain. Around one-third of ICUs do not have
continuous renal replacement therapy (CRRT) facility. Overall there was no major difference
in most common indications for RRT in different ICUs across the country, metabolic acidosis
being the most common indication for starting RRT in ICU, followed by rising creatinine and
hyperkalemia (64%, 32%, 30%, respectively). The intensivists across the ICUs in the country
did not have differences in initiating triggers for commencing RRT. Commonly used triggers
were early septic shock with acute kidney injury by 43% intensivists and early Kidney Disease
Improving Global Outcomes (KDIGO) stage 3 by 31%. Looking at the nonconventional uses of
ECT, 44% of responders had never used RRT for poisonings and only 21% of intensivists were
practicing ECMO for resuscitation (eCPR). One-fourth of intensivists are either not modifying
or sometimes modifying drug doses for patients undergoing ECT.
The survey highlighted that only 9% Indian ICUs are in public domain, against 50% being
in corporate sector and 41% being private setups and there was a statistically significant
difference in ICU beds in different sectors (p = 0.000). Availability of ECMO was also signifi-
cantly different according to the type of setup (p < 0.05). More than half of public sector and
private setups do not have ECMO facility as compared to 74% corporate settings having
ECMO. There was also a significant difference in intensivists’ preference of RRT modality in
hemodynamically unstable patients (p = 0.007). 63% of intensivists from corporate setups
preferred CRRT for such patients while only 55% of those working in public sector ICUs and
40% in private setups used CRRT. This might be because of limited availability of resources:
80% of corporate setups and 66% of public and private setups had CRRT facility, but this
difference was not statistically significant (p = 0.023). Financial consideration was another
major reason while deciding the choice of RRT. 54% intensivists considered high cost as sole
reason for not considering CRRT. A major difference in practice among public and private/
corporate sector intensivists was the preferred dialysis access (p = 0.000). Femoral access was
preferred by public sector (41%) while corporate and private sector physicians (81%, 71%)
preferred double-lumen jugular catheters. A significant difference was also observed in use
of RRT for poisonings. This indication was used for RRT mostly by corporate sector (40%)
while less commonly used by public (24%) or private sector (23%) (p = 0.005). There was a
significant difference in intensivist being ECMO team leader in corporate setups (61%)
while in public setups (38%) and 54% in private setups (p = 0.017).
Of the total Indian ICUs, 66% have been running teaching programs. On comparison of
teaching versus nonteaching ICU, there was a significant difference in availability of both
extracorporeal therapies (RRT and ECMO) in teaching versus nonteaching institutes. Only 37%
Chapter 1  Introduction to Extracorporeal Life Support 3
of nonteaching institutes had ECMO facility as compared to 72% in teaching hospitals
(p = 0.000). 54% of nonteaching ICUs had CRRT facility versus 82% of teaching institutes
(p = 0.000). When ECT practices were compared, very few nonsignificant differences were
observed.
Keeping in mind the results of survey, the practical aspects of ECT have been vastly
covered in the book. The book is divided into two sections: Section 1 including 23 chapters
widely covering theoretical and practical management of RRT including acute kidney injury
(AKI) epidemiology, setting up of RRT in ICU, different types of RRT available, modality
preference for specific ICU patients, how and when to initiate, prescription while starting
CRRT, troubleshooting, weaning from RRT, and managing nutrition. Altering the doses of
drugs during RRT should be a routine that needs to be inculcated into day-to-day practice.
To practically help the intensivists, we have included a separate chapter on drug dosing
during RRT. Recent uses of RRT like hemoperfusion in poisonings, therapeutic apheresis,
and ECT for sepsis have been included as separate chapters in the book. Section 2 covers
ECMO with 24 chapters including physiology of ECMO, indications and contraindications,
hardware, cannulation and priming of circuit, how to initiate, anticoagulation, monitoring,
sedation, ventilation during ECMO, weaning and complications of ECMO including ECMO
sepsis. It also includes unconventional topics like ECMO for poisonings, cardiac issues on
ECMO, nutrition during ECMO, and ECMO during cardiopulmonary resuscitation. Another
technical aspect of patients on ECMO is how to initiate CRRT during ECMO. This has
been included as a separate chapter. Both the sections have separate chapters focusing on
pediatric differences in RRT and ECMO. At the end of each section, multiple-choice questions
have been provided for the readers to self-assess their overall knowledge of the subject.
The role of ECT in the ICU is primarily to support specific organ dysfunction with multi-
organ failure. The strategies to employ it are dynamic and evolving. The ultimate goal of
this book is to further promote and practically help the critical care physicians handling
bedside ECT in ICUs in their day-to-day management of sick patients requiring specific
therapy and be a handy ready reckoner in times of trouble for them. The book will be a great
help for critical care students, freshers joining ICUs, and can even at times be a troubleshooter
for senior intensivists. It will provide insight into the ECT for general physicians, dialysis
technicians, cardiac anesthetists, and perfusionists handling dialysis or ECMO machines.
The society also wishes to promote research into AKI, RRT, and ECMO in critically ill
patients, which is as of now lacking in Indian ICUs. A national registry database capturing
the detailed information of ICU patients requiring RRT and ECMO can be the way forward to
look into Indian ICU practices and aim for quality improvement. We sincerely hope that the
book serves its purpose and is read by the intensivists not only in India but across the globe.
HAPPY and FRUITFUL READING!!
SECTION 1
Renal Replacement Therapy

Managerial Aspects of setting up Renal Replacement


‰‰ Monitoring during Continuous Renal Replacement
‰‰
Therapy in Intensive Care Unit Therapy
Kanwalpreet Sodhi, Rajan Isaac, Manvi Narang Abdul Samad Ansari, Mayur S Shah, Shashank MR
AKI in ICU: Epidemiology and Causes
‰‰ Switch Over from or Termination of Continuous Renal
‰‰
Sree Bhushan Raju, Anvesh Golla, Sonu Manuel Replacement Therapy
Types of Renal Replacement Therapy in ICU Ajith Kumar AK, Topoti Mukherjee
‰‰
Gopal Raval, Amrish Patel, Tushar Patel Continuous Renal Replacement Therapy in Specific
‰‰
Principles of Renal Replacement Therapy: Practical Situations/Diseases
‰‰
Applications Prakash Jiandani, Gunjan Chanchalani
KC Prakash, S Balasubramanian Nutrition during Renal Replacement Therapy
‰‰
Indications for Renal Replacement Khalid Ismail Khatib, Subhal Bhalchandra Dixit
‰‰
Therapy in ICU: Renal and Nonrenal Drug Dosing in Continuous Renal Replacement
‰‰
Nita George, Vilesh Valsalan Kalthoonical Therapy
Initiation of Renal Replacement Therapy in Intensive Ranajit Chatterjee, Priyanka H Chhabra
‰‰
Care Unit Troubleshooting in Renal Replacement Therapy
‰‰
Ashish Nandwani, Vijay Kher Kanwalpreet Sodhi, Niraj Tyagi, Diptimala Aggarwal,
Sumati Verma
Slow Low-efficiency Daily Dialysis in ICU
‰‰
Joyita Bharati, Raja Ramachandran, Vivekanand Jha Peritoneal Dialysis in Intensive Care Unit
‰‰
KS Nayak, SV Subhramanyam, Praveen K Etta, S Antony
Continuous Renal Replacement Therapy: Know the
‰‰
Machine Hemoperfusion for the Treatment of Poisoning
‰‰
Simant Jha, Sameer Bhuwania, Sanjeev Saxena Ganshyam Jagathkar, Nandhakishore Jampala,
Chandreshkumar Sudani
Continuous Renal Replacement Therapy Prescription
‰‰
in ICU Therapeutic Apheresis
‰‰
Girish V Kumthekar, Jyothsna Guttikonda, Rajasekara Vaishali Solao
Chakravarthi M Extracorporeal Therapies in Sepsis
‰‰
Anticoagulation in Continuous Renal Replacement
‰‰ Yash Javeri, Ravi Jain, Sandesh KJ
Therapy Renal Replacement Therapy in Children
‰‰
Pratheema Ramachandran, Ramesh Venkataraman Anil Sachdev, Kanav Anand
Goals of Continuous Renal Replacement Therapy in ICU
‰‰ MCQs on Renal Replacement Therapy
‰‰
Sunitha Binu Varghese, Snehal Gaikwad Ravi Jain, Rohit Yadav, Yash Javeri
CHAPTER 2
Managerial Aspects of setting up Renal
Replacement Therapy in Intensive Care Unit
Kanwalpreet Sodhi, Rajan Isaac, Manvi Narang

INTRODUCTION
Acute kidney injury (AKI) was earlier largely thought of as a marker of mortality for critically ill
patients but not so now. Renal replacement therapy (RRT) is now being routinely offered as a
treatment for AKI. RRT is a day-to-day procedure in modern intensive care units (ICUs), which
can be done in several different ways: intermittent hemodialysis (IHD), continuous renal
replacement therapy (CRRT), and slow low-efficiency daily dialysis (SLEDD). The use of RRT in
conjunction with other therapies [i.e. plasmapheresis, extracorporeal membrane oxygenation
(ECMO), molecular absorbent recirculating systems (MARS)] is also increasingly being
used in both pediatric as well as adult ICUs. With critical care medicine reaching its zenith,
the role of the critical care team in managing RRT in the ICU has become significant. The
ICU team must possess the required knowledge and experience to ensure the effectiveness
of RRT and optimization of the programmatic aspects of RRT. In this current chapter, we will
be discussing the managerial and administrative aspects of setting up and effectively running
RRT program in ICU.

INFRASTRUCTURE
■ While planning RRT in ICU, scope of services should be clearly defined to guide the
service providers.
■ The ICU must be planned in a way that it is equipped to provide different modalities of
RRT including appropriate dialysis machines, inbuilt electrical installation with backup,
water port with RO/ultrapure water and effluent drainage system.
■ The equipment should also be able to support other therapeutic modalities like plasma-
pheresis, ECMO, and molecular absorbent circulating systems.
■ There are no definitive recommendations to guide the number of dialysis beds in the ICU.
In ICU patients, considering the incidence of AKI and the need for RRT, 1–2 beds per 10 ICU
beds can be considered reasonable.
■ Minimum space requirements should be met with to ensure easy and accessible work flow.
■ Location of nursing station should be such that surveillance and monitoring of patients
on hemodialysis are adequate.
8 Section 1  Renal Replacement Therapy

■ Clearly defined policy with isolation facility for reactive patient’s management is must.
■ Establish a documented maintenance system for critical equipment and a preventive
and breakdown maintenance log of all defined equipment to be maintained.

MANPOWER
Role of the Nephrologist and Critical Care Physician
■ In current scenario, starting RRT in ICU is a joint venture of intensivist in-charge and the
nephrologist.
■ Teamwork and collaboration of intensivist and nephrologist bring out the best outcomes
for the patients.
■ The consultant who initiates the RRT in ICU needs to be committed toward acquiring
and maintaining:
– Basic concepts of renal physiology with clarity
– Expertise in diagnosis and management of AKI
– Understanding the risks and benefits; and strengths and weaknesses of the different
acute RRT modalities, so that most appropriate therapy is successfully applied for
specific requirements of a patient.
– Balancing the risk and benefits of initiating versus withholding RRT.
– Right prescription leading to maximal efficacy and minimal complications.
– Comprehension of fundamental aspects of critical care physiology and the interactions of
RRT with critical illness (i.e. drug dosing and nutrition needs during RRT, etc.).

RRT Program Leadership


The institution must establish an administrative leader with clinical experience in handling
critically ill AKI patients and who must be well versed in managing technical aspects of RRT.
The administrative head needs to put time and efforts, which involves providing infrastructure,
to engaging ICU heads and teams, defining and implementing quality protocols and evolving a
well-defined culture to maximize favorable outcomes.

Role of Team
Crux of a successful RRT program is a team strengthened by multidisciplinary experts, who
ensure highest quality with a cost-effective management.
■ Core team should have members from nephrology, ICU team, nursing, and pharmacy.
■ There are various options of successful nursing models for RRT program—e.g. utilization of
only dialysis nurses, only ICU nurses or a combination of both—and at institutional level,
it needs to be decided which model works best for their unit.
Division of duties, training and updating staff, identifying and managing complications,
maintenance schedule and ensuring administrative support are some of the key challenges in
implementing RRT in ICU.
■ Regular meetings and collaboration is must for RRT team to do timely follow-up of
incidents, unit standard operating procedures (SOPs), procedures, and ensure dispersal
of information.
Chapter 2  Managerial Aspects of setting up Renal Replacement Therapy in Intensive Care Unit 9
■ The team should conduct regular assessments of staff training, as well as reviews of
competencies, staff satisfaction, handling complications, uniformity of care, and cost-
effectiveness.

COMPETENCY AND EDUCATION PROGRAM IN RRT


Though doctors’ and nurses’ competency for RRTs has not been described and there is a wide
extent of training needs differing from unit to unit, institutional standards should be developed as
per specific requirements and regular reassessments should be conducted to check compliance.
■ A documented training program for the staff, e.g. induction trainings, job orientation
program for existing policies and protocols, on the job supervision and trainings, and
continuing education with skill enhancement, should be there.
■ Trainings shall be conducted for the medical, nursing, paramedical, as well as support staff.
■ The team must be educated on issues related to timing of starting and stopping RRT,
modality selection, RRT prescription, as well as complications related to RRT.
■ Junior doctors, nursing personnel, and ICU technicians need to be educated in recent
developments in AKI, consensus AKI definitions, link between fluid overload and mortality,
long-term complications of AKI, care of patients with severe electrolyte imbalance, AKI,
chronic kidney disease (CKD), and end-stage renal disease (ESRD). For this purpose,
continuous regular trainings should be conducted by means of clinical rounds and
interpersonal interactions and communications. Best is to make such topics as part of
educational curriculum to meet with training needs.
■ RRT care team should also be trained regarding the specific care for the ESRD population,
including topics concerned with vascular access, adequacy of dialysis, and continuation
of chronic medications.
■ Cardiovascular and infectious risks in CKD and renal transplant patients should also have
specific focus.
■ Staff must be trained for significance of alarms and ways to address alarms.
■ Regular simple assessments shall be done to test learning, competency, and to build the
confidence of the care providers.
■ Use of high-fidelity simulation-based scenarios, as an intervention to evaluate the know-
ledge and skills of nurses, helps to improve the satisfaction and improves understanding
of RRT principles as well as nurture critical thinking skills.
■ Interdisciplinary collaboration, ongoing training programs, and mentorship by expe-
rienced seniors are a must for a safe, successful, and effective RRT program.

RRT HARDWARE REGULATION


■ There are various types of machines for different RRT modalities.
■ In depth, knowledge is required to determine which machines, filters, anticoagulation, and
dialysis/replacement solutions are to be available in the hospital as per the patient types,
patient load, and the infrastructure of the ICU.
■ Important goal is to choose appropriate anticoagulation method most suitable to minimize
the risk of likely complications. Though making use of more than one type of anticoagulation
10 Section 1  Renal Replacement Therapy

can permit for a well-structured plan suitable to the individual patient needs yet at the
same time, it may make the program design more complex for providing care.
■ Analysis of water shall be done at least monthly for bacteria and 6 monthly for chemicals.
Biologically and chemically compatible continuous water supply shall be maintained.

DEVELOPMENT OF PROTOCOLS AND PROCEDURES


■ Following clinical guidelines by means of algorithms help in guiding even the ICU staff
to start RRT, monitoring the therapy, emergency management of any untoward incident,
troubleshooting and alerting the dialysis nurse or unit in-charge whenever there is a
problem, which cannot be addressed by simple algorithms.
■ Responsibility of developing protocols and policies is to be shared by intensivist, nephro-
logist, the administrative head with ICU and dialysis nurses involved in RRT to ensure
practical conjunction with the written guidelines.
■ Medical record documentation is of prime importance; communication to patient and
relatives shall be done clearly and documented.
■ Informed consent shall be taken before proceeding with RRT.
■ Standard operating procedures and protocols should be defined to provide uniform care
in most situations, while catering to specific requirements of patients.
■ Checklists can be developed for serving as step-by-step guide or troubleshooting.

DEVELOPMENT OF QUALITY IMPROVEMENT PROGRAMS


Monitoring for quality indicators and quality improvement in RRT program is a challenging
task as:
■ RRT is often delivered across different ICUs and each specialty ICU has a specific way
in which collaboration is done with nephrology unit, varying criteria for initiating RRT,
skills and expertise of nurses, patient characteristics, and patient volume.
■ No defined standards of care for defining nursing competency for RRT exist.
■ Acutely ill patient populations inherently have high mortality, and therefore, errors
related to RRT can be easily missed.
■ Currently, there are only few specific parameters to measure RRT care quality. Also as there
are varied practices in RRT, all metrics might not be uniformly applied for all.
Therefore, a standardized course or mechanism for collecting, analyzing, reporting, and
distributing RRT data is an essential mark of quality improvement. Potential quality para-
meters in RRT care are:
■ Patient outcome related—mortality, patient safety events/medical errors, and dialysis
catheter-related bloodstream infections.
■ RRT prescription related—prescribed and delivered effluent dose, filter circuit life,
filter clotting and unplanned or out of schedule filter replacement, fluid removal goals
achievement, and need for electrolyte supplementation.
■ Process related—time between RRT order and initiation, causes of delayed initiation.
■ Competency assessment—initiating basics orientation training of nurses and physicians,
maintenance specifications and standards compliance.
Chapter 2  Managerial Aspects of setting up Renal Replacement Therapy in Intensive Care Unit 11
■ Though mortality is an evident indicator that should be captured and analyzed, it may
be tough task to attribute mortality or survival exclusively to any one procedure in the
critically ill patients with complex physiology. Few evidence-based metrics available
for quality improvement process of RRT are:
■ Delivered effluent dose: Defined target of 20–25 mL/kg/h in adults.
■ Circuit filter life: Circuit life is a crucial metric to assess the full program.
– Assess the appropriateness of catheter placement
– Adequacy and appropriateness of anticoagulation given
– Was the RRT prescription suitable to achieve and maintain circuit patency?
– Was the nurse able to timely contain, report, and troubleshoot alarms?
■ Monitoring of complications like bleeding, citrate lock, infections, etc. and incidents
related to patient safety are other major facets of the quality improvement measures.
Renal replacement therapy centers should conduct a check and reassessment survey so
as to have a root cause analysis for any adverse or patient safety incident. As more ICUs will
commit to perform and improve quality in their RRT programs in the future, benchmarks
can be defined and implemented; and processes and protocols with uniform outcomes,
productivity, safety, benefits, and cost-effectiveness can be identified and adapted.

CONCLUSION
For establishing a successful RRT program in ICU, the basic requirements are:
■ Multidisciplinary team with clearly defined roles and responsibilities
■ Appropriate infrastructure
■ Defined protocols
■ Informed consent
■ Continuing education programs and trainings
■ Backup for all critical modalities
■ Preventive and breakdown maintenance program
■ Continuous quality improvement program.

SUGGESTED READING
1. Bhowmik D, Tiwari SC. (2012). Challenges of hemodialysis in India. [online] Available from: http://
medind.nic.in/jav/t12/i2/javt12i2p99.pdf. [Last accessed October, 2019].
2. Clark WR, Neri M, Garzotto F, et al. The future of critical care: renal support in 2027. Crit Care.
2017;21(1):92.
3. Directorate General of Health Service Government of India. (2010). Guidelines for Dialysis Centre.
[online] Available from: https://mohfw.gov.in/sites/default/files/74917583801426158301.pdf. [Last
accessed October, 2019].
4. Golestaneh L, Richter B, Amato-Hayes M. Logistics of renal replacement therapy: relevant issues
for critical care nurses. Am J Crit Care. 2012;21(2):126-30.
5. Mehta RL. Challenges and pitfalls when implementing renal replacement therapy in the ICU. Crit
Care. 2015;19 (Suppl 3):S9.
6. Pannu N, Noel Gibney RT. Renal replacement therapy in the intensive care unit. Ther Clin Risk
Manag. 2005;1(2):141-50.
7. Ronco C, Bellomo R. Dialysis in intensive care unit patients with acute kidney injury: continuous
therapy is superior. Clin J Am Soc Nephrol. 2007;2(3):597-600.
CHAPTER 3
AKI in ICU: Epidemiology and Causes
Sree Bhushan Raju, Anvesh Golla, Sonu Manuel

INTRODUCTION
Acute kidney injury (AKI) is a serious and common health issue in critically ill individuals.
Robust clinical data identifies AKI as a heterogeneous syndrome with different etiologies
often multifactorial.1 Incidence of AKI is on the rise and it is associated with high morbidity
and mortality.2 AKI can also lead to either new onset or faster progression of chronic kidney
disease (CKD). Detailed knowledge of the epidemiologic characteristics of AKI in critically
ill patient is essential to optimize management decisions and for formulation of AKI public
health policy.

DEFINITION
William Heberden in 1802 described total suppression of urine as “ischuria renalis”. It was the
earliest description of AKI in medical literature. Since then, almost 35 different definitions
of AKI were used.3 In 2004, Bellomo et al.4 developed the RIFLE classification system of AKI,
which was later modified by AKIN group of investigators as AKIN classification.5 The latest
classification system of AKI was proposed by Kidney Disease Improving Global Outcomes
Group (KDIGO) in 2012.6 According to this, AKI is defined by either an increase in serum
creatinine (>0.3 mg/dL within 48 hours or >1.5 times above baseline in 7 days) or an episode
of oliguria (urine volume <0.5 mL/kg/hour for 6 hours). AKI is divided into three stages by
worst of either serum creatinine or changes in oliguria. Currently, most of the published
literatures utilize one of these systems.

EPIDEMIOLOGY
The incidence of AKI worldwide is not well known because of differences in definition,
underreporting, and disparities between regions. Current uniform definitions of AKI have
allowed for more consistent estimates of epidemiology. Xue JL et al.7 described the incidence
of AKI in hospitalized Medicare beneficiaries between 1992 and 2001 and found an incidence
Chapter 3  AKI in ICU: Epidemiology and Causes 13
rate of 23.8 cases per 1,000 discharges, with approximate 11% increase per year. Almost around
the same time, data from Spain by Liano F et al. described an overall incidence of AKI of 209
cases per million population.8 Ali et al.9 conducted a population-based study in Scotland and
reported a higher incidence of 1,811 cases per million population during 2003. The analysis
of ANZICS data by Bagshaw et al.10 from 57 intensive care units across Australia from January,
2000 to December, 2005 showed an incidence of AKI as 36.1%. Various other studies note the
incidence of AKI in ICU varying from 10.8 to 78.2. This wide disparity in incidence rates and the
increasing frequency of the AKI make us concerned about the real magnitude of the problem.
Jha et al.11 in 1992 described the incidence of AKI in North India during 1-year period as
6.4 per thousand admissions. In 2007, Kohli et al.12 conducted a prospective study on AKI,
which noted an incidence of AKI as 294 in 33,301 patients (0.88%) admitted during the study
period. More recently, a prospective, observational study from June, 2013 to October, 2015
in Puducherry, India reported an AKI incidence of 1.45% in critically ill patients in ICU.13
In 2018, Hwang S et al.14 observed an overall incidence of AKI in South Korea as 8.0%
and rise in crude incidence of AKI from 7.4% in 2008 to 8.3% in 2015.
Data from the developed world identifies AKI predominantly in the elderly population,7
but in developing world, AKI is seen predominantly in younger population. Most of the Indian
data had reported the mean age of patients varying from 40 years to 60 years.10,15 Sharma
et al.16 reported a considerably lower age of 28.6 years, in a cohort of predominantly elective
postsurgical patients and Priyamvada et al.13 from Puducherry also reported a younger cohort
with few comorbidities. Important socioeconomic implications are there for AKI in young
since the disease affects the rural males in their productive peak. Pediatric population is also
more affected in the developing world with some series reporting >15% of children with AKI.17
Incidence of AKI was seen more commonly in medical patients rather than surgical patients.10
Presence of multiple comorbidities such as cardiovascular disease, diabetes mellitus,
hypertension, chronic liver disease, and malignancy can lead to higher chance of developing
AKI. High severity of illness scores at admission has also been associated with high incidence
of AKI.9
Male–female ratio of AKI in developed world is almost 1:1 in most of the published
literatures. In developing nations, ratio changes to 1.8:1 (male:female children) and 5:1
(elderly males:elderly females). This disparity may not be due to difference in true incidence
but rather reflects the better treatment access for males in developing world. A series on
pediatric patients with AKI requiring RRT by Kandoth PW et al.18 in 1994 reported that 67%
of boys but only 24% of girls are brought to hospitals within 48 hours of the onset of anuria.
But the socioeconomic atmosphere is changing in developing nations providing better
treatment facilities to all.
Nearly one-third of patients admitted to ICU developed AKI within first 48 hours as
reported by Bagshaw et al.10 in 2008. This will have an important impact on healthcare
resources. Renal replacement therapy (RRT) is one of the mainstays of treatment for AKI.
Hsu R et al.19 reported that from 2000 to 2009, the incidence of AKI requiring dialysis in united
states increased from 222 to 533 cases per million person-years, averaging an increase of
10% per year. This data was in concordance with reports from other regions around the world,
which noted rise in incidence of dialysis requiring AKI.20 Singh T et al.21 in 2013 reported
14 Section 1  Renal Replacement Therapy

20.5% of AKI in ICU needed dialysis; other recent Indian studies by Priyamvada et al.13 and
Eswarappa et al.22 also had similar rates of requirement of RRT, 30.5 and 37.1, respectively.
However, this data is in contrast to prior reported data by Mahajan et al.15 in 2006 who noted
71.1% requirement of RRT. Peritoneal dialysis (PD), intermittent hemodialysis (IHD), and
continuous renal replacement therapy (CRRT) are all employed in the management of AKI
depending on patient’s characteristics and health resources available. In the Indian literature,
IHD is the commonly used method.13,15,22 Peritoneal dialysis is a realistic alternative for
resource-poor countries and its efficacy in management of AKI is widely reported.23
Even in developed countries, mortality associated with AKI remains high in spite of
improvements in management strategies. A meta-analysis on world incidence of AKI by
Susantitaphong P et al.24 noted a pooled AKI-associated all-cause mortality rate of 23% (13.8%
in children and 23.9% in adults). But a prior multicentric multinational study by S Uchino
et al.25 reported a much higher mortality rate of 60.3%. In various Indian studies, mortality
from AKI showed large variability from as low as 9.8% to as high as 90%.26,27 Majority of the
investigators reported a mortality rate in excess of 50%.13,15 The overall mortality of children
hospitalized with AKI ranges from 20% to 41.5%, but there is a very strong association
between etiology and mortality in children.17
The outcomes of AKI vary from complete recovery of renal functions to development of
either CKD or end-stage renal disease (ESRD). AKI can also contribute to long-term proteinuria
and cardiovascular diseases. Chertow et al.28 demonstrated in a cohort of critically ill patients
with AKI who required RRT that 33% of the survivors were still requiring dialysis after 12
months. In the Acute Renal Failure Trials Network Study,29 which enrolled 1,124 patients
with severe AKI, 25% survivors were dependent on RRT at the end of 2 months. However,
in contrast, an Australian study of 1,508 patients with severe AKI reported that only 5.4% of
survivors still required RRT by 3 months.30 Ali et al.9 had demonstrated that when the patients
with in-hospital mortality were excluded, full recovery of renal function was seen in 92.5%,
likely to reflecting the fact that almost all of the patients would have had acute tubular necrosis
(ATN), which then recovered. In contrast, renal functions came back to previous levels in only
65% of those who had background CKD. In the Indian literature, Mahajan et al.15 reported
15 of the 16 surviving patients in their cohort became dialysis dependent in 2006. However,
recent study by Eswarappa et al.22 has shown excellent renal recovery with 60.0% (n = 300)
of the patients recovering normal renal function, and when deceased patients were excluded,
96.15% patients had complete renal recovery.

ETIOLOGY OF ACUTE KIDNEY INJURY


Determination of exact etiology of AKI is important in deciding specific management strategies,
but this is complicated by the fact that AKI in critically ill patient is often multifactorial. The
time-honored classification of AKI to prerenal azotemia, intrinsic renal diseases, and post-
renal causes (Table 1) provides a conceptual framework for investigation of pathophysio-
logical mechanisms. In the study by Liano F et al.8 in 1996, the most frequent causes of acute
renal failure (ARF) were ATN (45%), prerenal (21%), acute-onset chronic renal failure (12.7%),
and obstructive ARF (10%). In 2005, an international multicenter study by Uchino et al.25
Chapter 3  AKI in ICU: Epidemiology and Causes 15

Table 1: Etiology of acute kidney injury.


Prerenal causes
Hypovolemia Diarrhea, hemorrhage, renal fluid loss, and third space loss
Decreased cardiac output Cardiogenic shock, MI, arrhythmia, and cardiomyopathy
Systemic vasodilatation Sepsis, anaphylaxis, and adrenal cortical insufficiency
Renal vasoconstriction Drugs (NSAIDs, ACE/ARB), hepatorenal syndrome
Intrinsic renal causes
Vascular Renal artery/vein thrombosis, aortic dissection, cholesterol emboli,
vasculitis, TTP, HUS, and DIC
Glomerular RPGN, ANCA vasculitis, IRGN, anti-GBM disease, lupus nephritis,
cryoglobulinemia, and HSP
Interstitial Drugs (penicillin, fluoroquinolones, thiazides, and allopurinol), AIN, renal
abscess, sarcoidosis, and lymphoma
Postrenal causes
Intratubular Crystals (uric acid, oxalic acid, acyclovir, and sulfonamides), protein
deposition (myoglobin, hemoglobin, and light chains)
Ureteral obstruction Nephrolithiasis, strictures, malignancy, and retroperitoneal fibrosis
Lower urinary tract obstruction BPH, prostate malignancy, bladder carcinoma, and strictures
(ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; AIN: acute interstitial nephritis;
DIC: disseminated intravascular coagulation; GBM: glomerular basement membrane; HUS: hemolytic-uremic
syndrome; HSP: Henoch–Schönlein purpura; IRGN: infection-related glomerulonephritis; MI: myocardial
infarction; NSAID: nonsteroidal anti-inflammatory drug; RPGN: rapidly progressive glomerulonephritis;
BPH: benign prostatic hyperplasia)

reported sepsis as the most prevalent underlying cause for AKI (47.5%), other causes of AKI
in their study were major surgical intervention (34.3%), cardiogenic shock (26.9%), hypo-
volemia (25.6%), drug-induced nephrotoxicity (19%), hepatorenal syndrome (5.7%), and
obstruction (2.6%). This data is in concordance with other published literature from around
the world, which identifies sepsis and septic shock as the most important causes of AKI in
more than 50% of critically ill patients in ICU.31 The common mechanism of AKI in sepsis is
thought to be tissue hypoperfusion and renal ischemia. However, the recent studies indicate
that in a significant proportion of patients, AKI can occur in the absence of tissue hypo-
perfusion, suggesting that other mechanisms like cellular bioenergetic responses to injury,
diffuse microcirculatory flow abnormalities, and inflammation may be at work.32
In the developed world, trauma and surgery precede the onset of AKI in about 60% of cases,
closely followed by drugs, toxins (18–33%), medical diseases (30–35%), and gyneco-obstetric
complications in 5–10% patients.33 AKI in the developing world occurs predominantly
due to medical reasons such as volume-responsive renal failure, obstetric complications,
infections, and toxins.17 Major infections associated with AKI in tropics are malaria, dengue,
and leptospirosis. In one of the earliest Indian studies, the “Chandigarh Study” by Jha et
al.,11 nephrotoxic drugs (29%), decreased renal perfusion (21%), major surgery (18%), and
16 Section 1  Renal Replacement Therapy

septicemia (17%) were the most frequent causes of AKI. Singh et al.21 reported prerenal as the
most common form of hospital-acquired AKI (HAAKI) in both the medical and surgical units,
whereas ATN and prerenal were seen equally in ICUs. In the description of spectrum of
AKI in critically ill by Eswarappa et al.,22 the most common cause of AKI was sepsis (38%).
Gastroenteritis (10.4%) was the second most common cause of AKI followed by obstetrical
diseases, while surgical, hepatic, and cardiac disease constituted the other major causes.
Malaria, dengue, and leptospirosis contributed to 6% of AKI. Several studies have described
the incidence and causes of AKI in patients with HIV over the past two decades, especially
with the advent of ART. Major causes of AKI in HIV include sepsis, medications, immune
restoration inflammatory syndrome, rhabdomyolysis, HIV-associated nephropathy (HIVAN),
and obstruction.34
Renal AKI develops when the primary cause of AKI is parenchymal injury, caused by
drugs, toxins, and ischemia. Nephrotoxic drugs have been implicated as etiologic factors
in 17–26% of in-hosital AKI, patients specific risk factors for drug nephrotoxicity are female
sex, older age, hyperbilirubinemia, hypovolemia, and hypoalbuminemia.32 Glomerulus and
proximal tubule bear the maximum brunt of drug toxicity, but the different parts of kidney can
be affected by different drugs (Fig. 1).35 Developing countries have higher incidence of acute
glomerulonephritis (both primary and secondary to infectious diseases) than in developed
countries.36 Postrenal causes of AKI such as urogenital malignancies and retroperitoneal
fibrosis are also more commonly reported in developing countries.

Fig. 1: Site-specific nephrotoxicity of drugs.


Chapter 3  AKI in ICU: Epidemiology and Causes 17

CONCLUSION
Acute kidney injury is a major public health issue with a rise in incidence over the past few
years especially in the critically ill patients admitted in ICU. AKI has detrimental effects on
overall survival of patients; in addition, it can lead to development or progression of CKD,
proteinuria, and cardiovascular diseases. AKI is a heterogeneous syndrome but sepsis is the
predominant cause in developing world. The best treatment of AKI is prevention but equally
important is avoidance of nephrotoxic agents and hemodynamic optimization.

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1. Moore P, Hsu R, Liu K. Management of acute kidney injury: core curriculum 2018. Am J Kidney
Dis. 2018;72(1):136-48.
2. Li P, Burdmann E, Mehta R; World Kidney Day Steering Committee 2013. Acute kidney injury:
global health alert. Intern Med J. 2013;43(3):223-6.
3. Kellum J, Levin N, Bouman C, et al. Developing a consensus classification system for acute renal
failure. Curr Opin Crit Care. 2002;8(6):509-14.
4. Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure—definition, outcome measures, animal
models, fluid therapy and information technology needs: The Second International Consensus
Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8(4):R204-12.
5. Mehta R, Kellum J, Shah SV, et al. Acute Kidney Injury Network: report of an initiative to improve
outcomes in acute kidney injury. Crit Care. 2007;11(2):R31.
6. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron. 2012;120(4):
c179-84.
7. Xue J, Daniels F, Star R, et al. Incidence and mortality of acute renal failure in medicare
beneficiaries, 1992 to 2001. J Am Soc Nephrol. 2006;17(4):1135-42.
8. Liaño F, Pascual J; The Madrid Acute Renal Failure Study Group. Epidemiology of acute renal
failure: a prospective, multicenter, community-based study. Kidney Int. 1996;50(3):811-8.
9. Ali T, Khan I, Simpson W, et al. Incidence and outcomes in acute kidney injury: a comprehensive
population-based study. J Am Soc Nephrol. 2007;18(4):1292-8.
10. Bagshaw S, George C, Dinu I, et al. A multi-centre evaluation of the RIFLE criteria for early acute
kidney injury in critically ill patients. Nephrol Dial Transplant. 2007;23(4):1203-10.
11. Jha V, Malhotra HS, Sakhuja V, et al. Spectrum of hospital-acquired acute renal failure in the
developing countries—Chandigarh study. Q J Med. 1992;83(303):497-505.
12. Kohli H, Bhat A, Jairam A, et al. Predictors of mortality in acute renal failure in a developing
country: a prospective study. Ren Fail. 2007;29(4):463-9.
13. Priyamvada PS, Jayasurya R, Shankar V, et al. Epidemiology and outcomes of acute kidney injury
in critically ill: experience from a tertiary care center. Indian J Nephrol. 2018;28(6):413-20.
14. Hwang S, Park H, Kim Y, et al. Changes in acute kidney injury epidemiology in critically ill patients:
a population-based cohort study in Korea. Ann Intensive Care. 2019;9(1):65.
15. Mahajan S, Tiwari S, Bharani R, et al. Spectrum of acute renal failure and factors predicting Its
outcome in an intensive care unit in India. Ren Fail. 2006;28(2):119-24.
16. Sharma H, Sural S, Sharma R, et al. Etiology, prognosis, and outcome of post-operative acute renal
failure. Ren Fail. 2000;22(1):87-97.
17. Cerdá J, Bagga A, Kher V, et al. The contrasting characteristics of acute kidney injury in developed
and developing countries. Nat Clin Pract Nephrol. 2008;4(3):138-53.
18. Kandoth PW, Agarwal GJ, Dharnidharka VR. Acute renal failure in children requiring dialysis
therapy. Indian Pediatr. 1994;31(3):305-9.
18 Section 1  Renal Replacement Therapy

19. Hsu R, McCulloch C, Dudley R, et al. Temporal changes in incidence of dialysis-requiring AKI.
J Am Soc Nephrol. 2013;24(1):37-42.
20. Hoste E, Schurgers M. Epidemiology of acute kidney injury: how big is the problem? Crit Care
Med. 2008;36(Suppl):S146-51.
21. Singh T, Rathore S, Choudhury T, et al. Hospital-acquired acute kidney injury in medical, surgical,
and intensive care unit: a comparative study. Indian J Nephrol. 2013;23(1):24-9.
22. Eswarappa M, Gireesh M, Ravi V, et al. Spectrum of acute kidney injury in critically ill patients:
a single center study from South India. Indian J Nephrol. 2014;24(5):280-5.
23. Chitalia V, Almeida A, Rai H, et al. Is peritoneal dialysis adequate for hypercatabolic acute renal
failure in developing countries? Kidney Int. 2002;61(2):747-57.
24. Susantitaphong P, Cruz D, Cerda J, et al. World incidence of AKI: a meta-analysis. Clin J Am Soc
Nephrol. 2013;8(9):1482-93.
25. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational,
multicenter study. JAMA. 2005;294(7):813-8.
26. Sural S, Sharma RK, Singhal MK, et al. Acute renal failure in an intensive care unit in India—
prognostic factors and outcome. J Nephrol. 1999;12(6):390-4.
27. Korula S, Balakrishnan S, Sundar S, et al. Acute kidney injury-incidence, prognostic factors, and
outcome of patients in an intensive care unit in a tertiary center: a prospective observational study.
Indian J Crit Care Med. 2016;20(6):332-6.
28. Chertow GM, Christiansen CL, Cleary PD, et al. Prognostic stratification in critically ill patients
with acute renal failure requiring dialysis. Arch Intern Med. 1995;155(14):1505-11.
29. Palevsky PM, Zhang JH, O’Connor TZ, et al. Intensity of renal support in critically ill patients with
acute kidney injury. N Engl J Med. 2008;359(1):7-20.
30. Bellomo R, Cass A, Cole L, et al. Intensity of continuous renal-replacement therapy in critically
ill patients. N Engl J Med. 2009;361(17):1627-38.
31. Mehta RL, Pascual MT, Soroko S, et al. Spectrum of acute renal failure in the intensive care unit:
the PICARD experience. Kidney Int. 2004;66(4):1613-21.
32. Mohsenin V. Practical approach to detection and management of acute kidney injury in critically
ill patient. J Intensive Care. 2017;5(1):57.
33. Lameire N, Van Biesen W, Vanholder R. Acute renal failure. Lancet. 2005;365(9457):417-30.
34. Gameiro J, Agapito Fonseca J, Jorge S, et al. Acute kidney injury in HIV-infected patients: a critical
review. HIV Med. 2018;20(2):77-87.
35. Bonventre J, Vaidya V, Schmouder R, et al. Next-generation biomarkers for detecting kidney
toxicity. Nature Biotechnology. 2010;28(5):436-40.
36. Singbartl K, Kellum J. AKI in the ICU: definition, epidemiology, risk stratification, and outcomes.
Kidney Int. 2012;81(9):819-25.
CHAPTER 4
Types of Renal Replacement Therapy in ICU
Gopal Raval, Amrish Patel, Tushar Patel

INTRODUCTION
Acute renal failure, also known as acute kidney injury (AKI), is defined as an abrupt (within 48
hours) reduction in kidney function. The AKI network defines the reduction in kidney function
as the presence of any one of the following:1
■ An absolute increase in serum creatinine of ≥ 0.3 mg/dL (≥26.4 μmol/L)
■ A percentage increase in serum creatinine of ≥ 50% (1.5-fold from baseline)
■ A reduction in urine output (<0.5 mL/kg per hour for more than 6 hours).
It is noted that a third patients in the critical care setting have an AKI2 and approximately 5%
of them will require renal replacement therapy (RRT).3 In-hospital mortality in patients with
an AKI requiring RRT is as high as 60%.4 The initial management of AKI involves treating the
underlying cause, stopping nephrotoxic drugs, and ensuring that the patient is in euvolemic
state, with an adequate mean arterial blood pressure. However, no specific treatments have
been shown to reverse the course of AKI, so RRT forms the basis of further management.

INDICATIONS FOR RRT


Acute kidney injury with:
■ Fluid overload (unresponsive to diuretics)
■ Hyperkalemia (K+ > 6.5)
■ Severe metabolic acidosis (pH < 7.1)
■ Rapidly climbing urea/creatinine (or urea >30 mmol/L)
■ Symptomatic uremia—encephalopathy, pericarditis, bleeding, nausea, and pruritus
■ Oliguria/anuria.
There is some suggestion that starting RRT early (defined as urea <27 mmol/L in the
PICARD study) may offer a survival benefit, however guidance on exact timing of RRT is still
lacking.5

TYPES OF RRT IN INTENSIVE CARE UNIT


■ Intermittent hemodialysis (IHD) and prolong intermittent renal replacement therapies (PIRRT)
20 Section 1  Renal Replacement Therapy

■ Continuous renal replacement therapies (CRRT):


– Continuous venovenous hemofiltration (CVVH)
– Continuous venovenous hemodialysis (CVVHD)
– Continuous venovenous hemodiafiltration (CVVHDF)
– Slow continuous ultrafiltration (SCUF)
– Continuous arteriovenous hemofiltration (CAVH)
■ Hybrid therapies, e.g. sustained low-efficiency dialysis (SLED).
The functional differences between the techniques listed above can be classified in terms
of:
■ The mechanism of solute removal (filtration versus dialysis)
■ The duration of the treatment (continuous versus intermittent).
Before understanding the different types of modality of RRT, one should understand the
following basic definition:
■ Convection: It is a solute transport across a membrane together with a solvent (usually
water) in response to a pressure gradient across the membrane.
■ Dalton: It is a unit of mass used to express atomic and molecular masses. It is the
approximate mass of a hydrogen atom, a proton, or a neutron.
■ Diffusion: It is a solute transport from a compartment with high concentration to a
compartment with low concentration.
■ Fick’s law of diffusion: It states that the rate of diffusion across a membrane is proportional
to the concentration gradient across that membrane.
■ Hydrostatic pressure: This is the pressure exerted by a fluid at equilibrium at a given point
within the fluid, due to the weight of the fluid above. In the context of hemofiltration, this
pressure is created by the rollerball pump system of the extracorporeal circuit.
■ Semipermeable membrane: It is a barrier, either cellulose or synthetic, that allows water,
electrolytes, and other molecules to pass through, while cellular components and larger
molecules are held on one side.
■ Ultrafiltrate: Plasma water and solutes that pass through the semipermeable membrane.
■ Ultrafiltration: Transport of water across a membrane by a pressure gradient.

MECHANISM OF SOLUTE REMOVAL


Filtration (Convection) versus Dialysis (Diffusion)
■ Hemofiltration involves blood being pumped through an extracorporeal system that
contains a semipermeable membrane. The hydrostatic pressure that is created on the
blood-side of the filter drives plasma water across the filter. This process is referred to as
ultrafiltration. Molecules that are small enough to pass through the membrane (<50,000
Daltons) are dragged across the membrane with the water by the process of convection. The
filtered fluid (ultrafiltrate) is discarded and a replacement fluid is added in an adjustable
fashion, according to the desired fluid balance (Fig. 1A).
■ Hemodialysis involves blood being pumped through an extracorporeal system that
contains a dialyzer. Blood flows through the dialyzer in one compartment, separated from
crystalloid solution (dialysate) in a second compartment, by a semipermeable membrane.
Solutes move across the membrane, down their concentration gradient (i.e. from high
Chapter 4  Types of Renal Replacement Therapy in ICU 21
concentration to low) from one compartment of the dialyzer to the other (Fick’s law of
diffusion). For example, bicarbonate moves from dialysate to blood, whereas urea and
potassium move from blood to dialysate. In order to maintain these essential concentration
gradients and enhance the efficiency of the system, the dialysate flows in the opposite
direction to the flow of blood (countercurrent). When removal of water is required, the
hydrostatic pressure on the blood side of the membrane is increased in order to force water
molecules into the dialysate compartment (Fig. 1B).
■ Hemodiafiltration is a combination of filtration and dialysis. There is no evidence to suggest
that CVVDF has a survival benefit when compared to CVVH, but it may be a useful way of
increasing clearance of small solutes.6,7
Slow continuous ultrafiltration is used when the only requirement is water removal.
Effectively, it is CVVH with a low filtration rate. It can remove up to 6 liters of fluid a day but
solute removal is minimal.

B
Figs. 1A and B: Schematic diagram comparing the different modes of solute removal in (A) Hemofiltration;
(B) Hemodialysis.
22 Section 1  Renal Replacement Therapy

Solute removal during RRT may occur by diffusing down a concentration gradient from
the blood across a semipermeable membrane into dialysate or by convective transport of
solute across the membrane during filtration. Fluid removal occurs by filtration, driven
by either a hydrostatic or osmotic pressure gradient across the semipermeable membrane.
In conventional IHD, the patient’s blood passes through a semipermeable hemodialyzer
countercurrent to the flow of dialysate on the other site of the membrane. The dialysis solution
has a composition that approximates the normal electrolytes conformation of extracellular
fluids and creates equilibrium to the blood, normalizing solutes. CRRT utilizes either diffusive
hemodialysis, convective hemofiltration, or combination of both. In addition to the duration
of therapy, the major difference between intermittent and continuous hemodialysis is the
dialysate flow rate. In intermittent hemodialysis, the dialysate flow rates (typically 500–800
mL/min) are equal to or greater than blood flow rates, allowing rapid solute clearance. In
continuous hemodialysis, the dialysate flow rate (typically 15–30 mL/min) is slow compared
to that of the blood, permitting virtual equilibration of low-molecular-weight solute such as
urea between the blood and dialysate. Thus, solute clearance for low-molecular-weight solutes
approximates the dialysate flow rate other than total daily or weekly clearances which is greater
with continuous treatment, due to the extended time of therapy.
In continuous hemofiltration, a high filtration rate is generated and physiologic replacement
fluid is administered at an equal rate, negative fluid balance (ultrafiltration) is accomplished
by administrating less mL per hour (normally 50–400 mL/h). Solute removal occurs exclusively
by convection, and clearance is approximately equal to the ultrafiltration rate. The convective
transport is limited primarily by the pore size of the membrane. So, hemofiltration provides
more efficient clearance of higher molecular weight (500–15,000 KD) solutes. Although it has
been proposed that removal of higher molecular weight with hemofiltration as compared to
hemodialysis would be of clinical benefit, this has not been borne out in clinical trials. Because
of their prolonged duration, the net ultrafiltration rate required to attend the same daily fluid
removal is lower with CRRT then with IHD. Thus, CRRT is generally considered to causeless
hemodynamic instability than conventional IHD.
Finally, PIRRT is a modification of conventional IHD, utilizing lower blood and dialysate
flow rate while prolonging the treatment duration to 8–16 hours.
There has been considerable debate regarding which modality is most appropriate for
use in critically ill patient with AKI, current data suggest that no individual modality of RRT
provides either better patient survival or recovery of kidney function. These modalities should
be complimentary and must not be considered as mutually exclusive. According to the KDIGO
guidelines, CRRT must be considered as the first-line treatment option in the hemodynamically
unstable patient and those with neurological illness who required RRT and might be prone to
developed cerebral edema.8,9

DURATION OF TREATMENT
Intermittent (IHD) versus Continuous (CRRT)
Intermittent hemodialysis involves dialyzing with higher flow rates than CRRT for defined
periods of time. A typical regime is 3–5 hours of dialysis three times a week. The high flow
rates and rapid fall in plasma osmolality mean that it is only suitable for patients who are
Chapter 4  Types of Renal Replacement Therapy in ICU 23
cardiovascularly stable. It forms the basis of long-term RRT for chronic renal failure and is not
commonly used in the critical care setting.
Continuous renal replacement therapy involves filtering and/or dialyzing on a continuous
basis. It allows better fluid management and creates less hemodynamic disturbance, but it is
more expensive than IHD and requires continuous rather than intermittent anticoagulation.
There is some evidence to suggest that CRRT is superior to IHD in patients with sepsis,
cardiovascular instability, or with a head injury. However, a large RCT comparing IHD with
CRRT, in patients with an AKI and multiple-organ dysfunction syndrome, showed no difference
in survival at 60 days.10
Sustained low-efficiency dialysis (SLED) is an example of a hybrid therapy, which aims
to combine the logistic and cost advantages of IHD with the relative cardiovascular stability
of CRRT. Treatments are intermittent but usually daily with longer session durations than
conventional IHD. Solute and fluid removals are slower than IHD, but faster than CRRT. Some
are confident that hybrid therapies are the future of RRT in ICU.

Which form of RRT should we use?


No single RRT technique has been shown to offer a survival benefit over the others in the
critical care setting, so the decision about which technique to use depends on:
■ What we want to remove from the plasma (Table 1)?
■ The patient’s cardiovascular status:
– CRRT causes less rapid fluid shifts and is the preferred option, if there is any degree of
cardiovascular instability.
■ The availability of resources:
– CRRT is more labor intensive and more expensive than IHD
– Availability of equipment may dictate the form of RRT.
■ The clinician’s experience:
– It is wise to use a form of RRT that is familiar to all the staff involved.
■ Other specific clinical considerations:
– Convective modes of RRT may be beneficial, if the patient has septic shock.
– CRRT can aid feeding regimes by improving fluid management.
– CRRT may be associated with better cerebral perfusion in patients with an acute brain
injury or fulminant hepatic failure.11,12

How the choice of RRT can be determined:

Table 1: The choice of renal replacement therapy (RRT).


Size of molecule
What do you want to remove? (Daltons) Example Preferred type of RRT
Small molecules/electrolytes <500 Urea, creatinine, K+, lithium Dialysis or filtration
Middle molecules 500–5,000 Large drugs like vancomycin Filtration better than
dialysis
Low-molecular weight proteins 5,000–50,000 Cytokines, complement Filtration
Water 18 Filtration better than
dialysis
(K: potassium)
24 Section 1  Renal Replacement Therapy

Schematic representation of CVVH and CVVHDF (Fig. 2):

Fig. 2: Circuits of continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration
(CVVHDF).

FILTERS
The properties of a filter that have an impact on its function are discussed here.

Biocompatibility
Biocompatibility is the degree to which the membrane will activate the patient’s inflammatory
and coagulation pathways. The greater the biocompatibility of a membrane, the less activation
it will cause.

Flux
Flux is the permeability of the filter. High-flux membranes are hydrophobic and may have
more or larger pores allowing more water and solute to move across the membrane.

Adsorption
Adsorption is the ability of larger solutes to adhere to the surface of the membrane. A highly
adsorptive membrane offers the potential benefit of adsorbing mid-sized molecules, including
inflammatory mediators, but only until it is saturated with them (usually after the first few
hours).

Thickness
Thinner membranes allow greater movement of solute by diffusion and also favor convective
movement.
Chapter 4  Types of Renal Replacement Therapy in ICU 25

Surface Area
The surface area of the membrane determines the available area for diffusion and ultrafiltration.
Filters are either cellulose-based or synthetic. Synthetic filters, such as polysulfone and
polyamide, are more biocompatible and are higher-flux membranes, so these seem more
suitable for CRRT; however, there is no conclusive evidence that they improve outcome. In
practice, most filters used for CRRT are synthetic, high-flux membranes with a surface area of
0.6–1.2 m2 and a pore size allowing the passage of molecules up to 50,000 Daltons.

REPLACEMENT FLUIDS
Replacement fluids vary slightly in their composition, but all are balanced salt solutions
with either a lactate or bicarbonate buffer. Lactate-based solutions are stable and, hence,
the cheaper and more practical option; however, their buffering capacity depends on the
conversion of lactate into bicarbonate. Under normal physiological conditions, the body
converts lactate into bicarbonate on an equimolar basis. This is not always the case in
critically ill patients, particularly if they have impaired liver function or already have a lactic
acidosis.
In these situations, RRT using a lactate-based replacement fluid can worsen the patient’s
acidosis, so a bicarbonate-based replacement solution should be used. If this is not possible
and serum lactate levels are not excessive then an alternative option is to continue with the
lactate-based replacement solution and commence an intravenous infusion of bicarbonate.
Bicarbonate-based replacement solutions have a more reliable buffering capacity, but need
to be prepared just prior to use. At present, there is no evidence to suggest that the choice of
replacement fluid has an impact on survival or renal recovery. Replacement fluid can be added
pre- or postfilter in varying ratios. The benefit of adding some of the replacement fluid prefilter
is that it lowers the hematocrit of the blood, which reduces the likelihood of the filter clotting.
The downside is that predilution reduces solute clearance and a compensatory increase in
flow rates should be considered (15% for ultrafiltration rates of 2 L/h and up to 40% for rates
of 4.5 L/h).

PHARMACOKINETICS WHILE ON RRT


When a patient is receiving RRT, drugs should be dosed if the glomerular filtration rate (GFR)
is 10–50 mL/min, but unfortunately, it is probably not this simple since there are numerous
variables. The most reliable guide to dosing is by measuring drug levels but this is not usually
a feasible option, so referring to the drug manufacturer’s recommendations is a reasonable
place to start.
The factors that affect the pharmacokinetics while on RRT are discussed here.

Protein Binding
Drugs that are highly protein bound (e.g. warfarin, diazepam, propranolol, and phenytoin)
are only cleared by RRT in small amounts. However, as the patient’s protein levels fall, the free
fraction of the drug increases along with its clearance.
26 Section 1  Renal Replacement Therapy

Size of Drug Molecule and Mode of RRT


Small molecules (<500 Daltons) are cleared by all (convective versus diffusive) types of RRT,
but as molecule size increases diffusion becomes less effective.

Timing of RRT
Drugs given between sessions of IHD or SLED (intermittent versus continuous) will not be
cleared until the subsequent session.

Dose of RRT
Reduced flow rates and/or shorter dialysis sessions will reduce clearance of drugs.

Membrane Permeability
The high-flux hemofilter membranes used in CRRT are permeable to most nonprotein-bound
drugs.

The Patient’s Residual GFR


This also needs to be taken into consideration.

PRESCRIPTION OF RRT
A typical prescription for a 75-kg patient requiring CRRT for an AKI would be as follows:13

Anticoagulation
■ Unfractionated heparin: 5,000 IU bolus followed by a prefilter infusion at 500 IU/h
■ Aim to anticoagulate filter but ensure activated partial thromboplastin time ratio
(APTTR) < 2.

Fluid Balance over 24 Hours


■ Aim for an even balance, if the patient is euvolemic
■ Aim for the appropriate negative balance, if the patient is fluid overloaded (<1,500 mL per
24 hours).

Type of Replacement Fluid/Dialysate


■ Use solutions without potassium, if serum potassium is high, but switch to potassium-
containing solutions as serum potassium normalizes.
■ Use a bicarbonate-based buffer rather than a lactate-based buffer, if there are concerns
about lactate metabolism or if serum lactate > 8 mmol/L.
– An intravenous bicarbonate infusion may be required, if a lactate-based buffer is used.

Exchange Rate/Treatment Dose


1,500 mL/h (75 kg × 20 mL/kg/h): The treatment dose is usually prescribed as an hourly
“exchange rate”, which is the desired hourly flow rate adjusted for the patient’s weight.
Chapter 4  Types of Renal Replacement Therapy in ICU 27

Exchange rate.
Hourly exchange
rate for 75 kg
Hourly flow rate (liter/hr) CVVH CVVHDF
Ultrafiltration rate Ultrafiltration Dialysate flow
(liter/hr) rate (liter/hr) rate (liter/hr)
Standard flow rate (20 mL/kg/hr) 1.5 1.5 0.75 0.75
High flow rate (35 mL/kg/hr) 2.6 2.6 1.3 1.3
(CVVH: continuous venovenous hemofiltration; CVVHDF: continuous venovenous hemodiafiltration)

In CVVH, the exchange rate simply represents the ultrafiltration rate; whereas in CVVHDF, it
represents a combination of the ultrafiltration rate and the dialysate flow rate. In CVVHDF,
the ratio of ultrafiltration to dialysate flow is often set at 1:1, but it can be altered to put the
emphasis on either the dialysis or filtration component.

CONCLUSION
Acute kidney injury is common and 5% of the critical care populations receive RRT. There
are various forms of RRT, but they all remove unwanted solutes by using the processes of
diffusion (dialysis) and/or convection (filtration). RRT can be administered continuously or
intermittently.
No single form of RRT has been shown to offer a survival benefit over the others, but there
are often other reasons why a particular technique may be preferable in a given situation. There
is some evidence that high-volume hemofiltration may improve survival in patients with septic
shock, but there have been no large randomized controlled trials in this area. The lifespan of
the circuit is dependent on good quality vascular access and appropriate anticoagulation.
Pharmacokinetics must be considered on an individual basis, but there are some general rules,
such as drugs, which are protein bound, are not easily removed. 60% of people receiving RRT
for AKI will die during that admission but 80% of the survivors will be free from RRT 1 year later.

REFERENCES
1. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: report of an initiative to improve
outcomes in acute kidney injury. Crit Care. 2007;11(2):R31.
2. Ostermann M, Chang RW. Acute kidney injury in the intensive care unit according to RIFLE. Crit
Care Med. 2007;35(8):1837-43.
3. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational,
multicenter study. JAMA. 2005;294(7):813-8.
4. Bagshaw SM, Laupland KB, Doig CJ, et al. Prognosis for long-term survival and renal recovery
in critically ill patients with severe acute renal failure: a population-based study. Crit Care.
2005;9(6):700-9.
5. Liu KD, Himmelfarb J, Paganini E, et al. Timing of initiation of dialysis in critically ill patients with
acute kidney injury. Clin J Am Soc Nephrol. 2006;1(5):915-9.
6. Honore PM, Jamez J, Wauthier M, et al. Prospective evaluation of short-term, high volume
isovolemic hemofiltration on the hemodynamic course and outcome in patients with intractable
circulatory failure resulting from septic shock. Crit Care Med. 2000;28(11):3581-87.
28 Section 1  Renal Replacement Therapy

7. Joannes-Boyau O, Rapaport S, Bazin R, et al. Impact of high volume hemofiltration on hemodynamic


disturbance and outcome during septic shock. ASAIO J. 2004;50(1):102-9.
8. Ratanarat R, Brendolan A, Piccinni P, et al. Pulse high-volume haemofiltration for treatment of
severe sepsis: effects on hemodynamics and survival. Crit Care. 2005;9(4):R294-302.
9. Cornejo R, Downey P, Castro R, et al. High-volume hemofiltration as salvage therapy in severe
hyperdynamic septic shock. Intensive Care Med. 2006;32(5):713-22.
10. Vinsonneau C, Camus C, Combes A, et al. Continuous venovenous hemodiafiltration versus
intermittent hemodialysis for acute renal failure in patients with multiple-organ dysfunction
syndrome: a multicentre, randomized trial. Lancet. 2006;368(9533):379-85.
11. Davenport A, Will EJ, Davison AM. Continuous vs intermittent forms of haemofiltration and/or
dialysis in the management of acute renal failure in patients with defective autoregulation at risk
of cerebral oedema. Contrib Nephrol. 1991;93:225-33.
12. Bellomo R, Cass A, Cole L, et al. Intensity of continuous renal-replacement therapy in critically ill
patients (RENAL study). N Engl J Med. 2009;361(17):1627-38.
13. Gatward JJ, Gibbon GJ, Wrathall G, et al. Standards and Recommendations for the Provision of
Renal Replacement Therapy on Intensive Care Units in the United Kingdom. Intensive Care Society
(2009). [online] Available from: ics.ac.uk. [Last accessed October, 2019].
CHAPTER 5
Principles of Renal Replacement Therapy:
Practical Applications
KC Prakash, S Balasubramanian

INTRODUCTION
Renal replacement therapy (RRT) is a modality of treatment, which replaces normal blood
purification functions of the kidneys in a clinical setting when the kidneys are nonfunctional.
There are various issues in critically ill patients.
■ Hemodynamically unstable on inotropes
■ Fluid overload due to various causes, which include large volume of fluid and inability
to be excreted due to reduced renal function or unable to be removed on conventional
dialysis due to hemodynamic instability
■ Severe metabolic acidosis
■ Coagulation abnormalities.
Ideal renal replacement treatment should be able to control volume status, correct
acid/base status, control uremic status while it should be free of complications, and should
improve renal and patient survival. This chapter shall deal in brief about the basic principles
of RRT.
The various types of RRT in the critical care unit (CCU) can be divided into intermittent,
hybrid, and continuous.
■ Intermittent RRT: Intermittent hemodialysis (IHD) and isolated ultrafiltration (IUF)
■ Hybrid RRT: Sustained (or slow) low-efficiency daily dialysis (SLEDD) and sustained (or
slow) low-efficiency daily dialysis with filtration (SLEDD-F).
■ Continuous RRT: Continuous venovenous hemofiltration (CVVH), continuous venovenous
hemodialysis (CVVHD), continuous venovenous hemodiafiltration (CVVHDF), and slow
continuous ultrafiltration (SCUF).
There are other extracorporeal therapies used in the ICU. These are:
■ Intermittent: Therapeutic plasma exchange
■ Continuous: High-volume hemofiltration (HVHF), pulsed high-volume hemofiltration
(PHVHF), ultra high-volume hemofiltration (UHVHF), and coupled plasma filtration and
adsorption (CPFA).
30 Section 1  Renal Replacement Therapy

PRINCIPLES OF RRT IN CCU


There are three fundamental principles in isolation or mostly in combination involved in RRT.
These are diffusion, ultrafiltration, and convection.

Diffusion
Diffusion is a process where solute molecules move from high-concentration solution to
low-concentration solution through a semipermeable membrane. Diffusion also can occur
with gases. Diffusion can be of two types—ordinary diffusion and forced diffusion. Ordinary
diffusion is defined as molecular movement caused by random movement seen in peritoneal
dialysis (PD). Forced diffusion occurs with external force, which acts on molecules to enhance
the process as seen in hemodialysis.

Factors Influencing Diffusion


■ Concentration gradient: As the gradient increases, diffusive clearance increases. Diffusion
ceases once the concentration between two compartments equalizes. In blood based
RRTs like IHD, SLED and CRRT, concentration gradient is maintained throughout the
process with continuous flow of dialysate which enables continuous diffusion, while in
PD concentration gradient decreases in due course of dwell time and hence diffusion
decreases (Fig. 1).
■ Blood flow rate (Qb) and dialysate flow rate (Qd): Increase in blood flow and/or dialysate
flow proportionately increase the diffusive clearance to a certain extent beyond which
it plateaus (Fig. 2). This is true for small molecular weight toxins only. The blood and
dialysate flow can be countercurrent (blood and dialysate flow in opposite directions)
or cocurrent (blood and dialysate flow in same direction). This prescription is based on
urea concentration and the rate at which it has to be removed in order to prevent rapid

Fig. 1: Diffusion.
Chapter 5  Principles of Renal Replacement Therapy: Practical Applications 31
removal, which could cause disequilibrium syndrome. Cocurrent flow causes diffusion to
be slower while countercurrent flow has higher diffusion capacity due to constant presence
of concentration gradient through the dialyzer (Figs. 3A and B).
■ Surface area of dialyzer and its efficiency: Each type of dialysis membrane has different
diffusive capacity and is referred as constant for that particular solute.
Small molecular weight toxins (urea and creatinine) are usually below 500 kDa and middle
molecules are between 500 kDa and 5,000 kDa. The smaller weight molecules are cleared
better with diffusion, based on the concentration gradient between the two compartments.
HD, SLED, CVVHD, and PD are predominantly diffusion-based therapies.
Middle molecules similar to vitamin B12 and beta-2 microglobulin do not diffuse easily but
transfer better by convection through solvent drag. Middle molecule clearance is membrane

Fig. 2: Effects on increasing blood and dialysate flows on diffusion of different solutes.

Fig. 3A: Cocurrent and countercurrent flows.


32 Section 1  Renal Replacement Therapy

Fig. 3B: Explaining urea diffusion by cocurrent and countercurrent.

limited and not dependent on blood and dialysate flow. Hemofiltration and hemodiafiltration
are convection-based therapies (latter also has additional component of diffusive solute
clearance).
The protein-bound solutes do not move easily with these modalities irrespective of their
molecular weights unless they have free fraction in the plasma and the ability of the protein-
bound fraction to dissociate.

Convection
It is a process in which solute moves along with the movement of water between two
compartments without change in the concentration of the solute during the transfer (a process
called solvent drag). Those solutes larger than the pore size of the membrane are held back and
the membrane acts like a sieve.

Ultrafiltration
The process by which water moves between the compartments due to pressure gradient
across the semipermeable membrane (i.e. the transmembrane pressure—TMP) is called
ultrafiltration (UF). There are two major types of pressures, which drive water movement:
■ Hydrostatic pressure: Water moves from a compartment with higher pressure to the one
with lower pressure (Fig. 4). This type of ultrafiltration occurs in all extracorporeal blood-
based RRT modalities, i.e. HD, SLED, SCUF, and continuous renal replacement therapy
(CRRT). Ultrafiltration by this process can be controlled and is near accurate.
Chapter 5  Principles of Renal Replacement Therapy: Practical Applications 33

Fig. 4: Convection with water movement by hydrostatic pressure.

Fig. 5: Convection with movement of water by osmotic pressure.

■ Osmotic pressure: Water moves from a compartment with lower osmotic pressure to the
one with higher pressure across a semipermeable membrane. This type of ultrafiltration
occurs in peritoneal dialysis (Fig. 5).

PRACTICAL APPLICATION OF VARIOUS TYPES OF RRT


Intermittent Therapies: Intermittent Hemodialysis and Isolated Ultrafiltration
Intermittent hemodialysis is predominantly a diffusion-based therapy combined with
ultrafiltration, if necessary, based on fluid status of the patient performed on hemodynamically
stable patients. Blood flow rates are between 200 mL/min and 350 mL/min. Dialysate flow rates
34 Section 1  Renal Replacement Therapy

are usually between 500 mL/min and 800 mL/min. Ultrafiltration volume can range between
1,500 mL and 5,000 mL over a 5-hour period.
Slow continuous ultrafiltration is predominantly ultrafiltration-based therapy but with
some amount of convective transport of solutes during UF. This process can be extended from
few hours to a day depending on the fluid status of the patient.

Hybrid Therapies—(New Terminology—PIRRT is Prolonged Intermittent Renal


Replacement Treatment), Sustained (or Slow) Low-efficiency Daily Dialysis, and
Sustained (or Slow) Low-efficiency Daily Dialysis with Filtration
Sustained (or slow) low-efficiency daily dialysis with filtration is routinely performed in the ICU
settings on hemodynamically unstable patients. The machine and the dialyzer used are the
same as HD. Blood flow rates are between 100 mL/min and 200 mL/min. Dialysate flow rates
are usually between 200 mL/min and 300 mL/min. Each session lasts between 6 hours and 8
hours. This also is a diffusion-based therapy with ultrafiltration depending on fluid status of
the patient. This is more slow and gentle process. Hence, the diffusion and ultrafiltration will
be slower compared to IHD.

Continuous Therapies: Continuous Venovenous Hemofiltration, Continuous


Venovenous Hemodialysis, Continuous Venovenous Hemodiafiltration, and Slow
Continuous Ultrafiltration
Continuous renal replacement therapy is also performed in ICU settings on hemodynamically
unstable patients with low blood flow rates of 100–200 mL/min. There are three types of CRRT.
Continuous venovenous hemodiafiltration involves large volumes of ultrafiltration
(around 20–40 mL/kg/hour), which enables pure convective clearance. As discussed earlier,
middle molecular solute clearance is the main purpose of this modality. This large-volume
ultrafiltration is compensated by giving replacement fluids.
Continuous venovenous hemodialysis (CVVHD) involves use of dialysate with smaller
volume ultrafiltration according to the patient’s fluid balance. This is purely a diffusion and to
some extent ultrafiltration-based therapy.
Continuous venovenous hemodiafiltration (CVVHDF) combines use of dialysate and
large-volume ultrafiltration, hence, requiring replacement fluids. This has both diffusion and
convection.
Peritoneal dialysis involves instilling hypertonic dialysate fluid through a catheter inserted
percutaneously or through laparoscope or surgically into the peritoneal cavity. The peritoneal
membrane acts as a semipermeable membrane. The solute removal is mainly by diffusion and
fluid removal is by osmotic pressure difference. These two mechanisms of transport depend
upon peritoneal permeability and vary from patient to patient hence unpredictable.

CONCLUSION
There are three different principles applied in combination or isolation in different ways in
treating critically ill patients. The modality of RRT is tailored as per the clinical condition and
Chapter 5  Principles of Renal Replacement Therapy: Practical Applications 35
requirement of the patient. These modalities can be changed from one to another based on the
patient’s clinical progress.

SUGGESTED READING
1. Daugirdas JT, Blake PG, Ing TS. Handbook of Dialysis, 4th edition. Philadelphia: Lippincott
Williams and Wilkins; 2007.
2. Golper TA, Fissell R, Fissell WH, et al. Hemodialysis: core curriculum 2014. Am J Kidney Dis.
2014;63(1):153-63.
3. Kellum JA, Bellomo R, Ronco C. Continuous Renal Replacement Therapy, 2nd edition. New York:
Oxford University Press; 2016.
4. Nissenson AR, Fine RE. Handbook of Dialysis Therapy, 5th edition. Philadelphia, PA: Elsevier;
2016.
5. Ricci Z, Romagnoli S, Ronco C. Renal Replacement Therapy. F1000Res. 2016;5:pii: F1000 Faculty
Rev-103.
CHAPTER 6
Indications for Renal Replacement
Therapy in ICU: Renal and Nonrenal
Nita George, Vilesh Valsalan Kalthoonical

INTRODUCTION
Acute kidney injury (AKI) is a major public health problem that affects millions of patients
worldwide and leads to decreased survival and increased progression of underlying chronic
kidney disease (CKD). The incidence of AKI in intensive care unit (ICU) setting is about 20–50%
and it directly impacts morbidity, length of hospital stay, and mortality.1 Renal replacement
therapy (RRT) plays a significant role in ICU in the treatment of renal failure, acute as well
as chronic, and also in nonrenal indications. RRTs in the form of intermittent hemodialysis
(IHD), continuous renal replacement therapy (CRRT), and peritoneal dialysis (PD) (mainly in
pediatric populations) are the modalities to tackle complications of AKI in ICU.

INDICATIONS (TABLE 1)
The treatment of AKI with RRT has the following goals:2
■ To maintain fluid and electrolyte, acid–base, and solute homeostasis
■ To prevent further insults to the kidney
■ To permit renal recovery

Table 1: Renal indications for initiation of renal replacement therapy.2


Absolute indications Relative indications Renal support
Refractory hyperkalemia (serum potassium > 6.5 mmol/L Solute control Volume control
not responding to medical management, rapidly rising
potassium or associated with cardiac toxicity)
Acidemia: Severe metabolic acidosis (pH is persistently Fluid removal Nutrition
<7.1 with serum bicarbonate level below 15 mEq/L)
Fluid overload causing pulmonary edema not responsive Correction of acid– Drug delivery
to diuretic therapy base abnormalities
Uremic complications: Blood urea > 150 mg/dL with Regulation of acid–base
(pericarditis, bleeding, and encephalopathy) and electrolytes status
Solute modulation
Chapter 6  Indications for Renal Replacement Therapy in ICU: Renal and Nonrenal 37
■ To allow other supportive measures (e.g. antibiotics and nutrition support) to proceed
without limitation or complication.

Renal Support
In situations where there is no clear indication for RRT, but when used as a form of renal
support, it helps to modify outcome in terms of hospital stay and mortality (Tables 2 and 3).
■ Nutrition plays a key role in outcome. Hypoalbuminemia is a known predictor of mortality.
In cases of oliguria, anuria, and fluid overload, CRRT helps in maintaining volume on
hourly basis. Enteral and parenteral nutrition can be continued while on CRRT without
causing fluid overload.
■ Ventilation can be improved by keeping the lungs dry, which helps in maintaining
oxygenation and early weaning from the ventilator.
■ Drug delivery and dose modification can be done easily when on CRRT as volume can be
adjusted with hourly ultrafiltration. Intravenous antibiotics can add a lot of volume to the
daily intake and this additional volume is well managed with CRRT.
■ Blood and blood products can be administered without causing fluid overload.
■ Electrolyte disturbances like hypernatremia and hypercalcemia can be corrected quickly
with dialysis.
These criteria are based on expert opinion rather than evidence arising from randomized
controlled trials since it is not possible to withhold lifesaving therapy from patients.

Table 2: Nonrenal indications for RRT.


Adult Pediatric
Toxins Inborn errors of metabolism
Sepsis Hypothermia
Congestive cardiac failure —
Liver support —
Cardiopulmonary bypass —
Hypothermia/hyperthermia —

Table 3: Poisons amenable to removal by extracorporeal therapies.


Hemodialysis CRRT Hemoperfusion* Plasmapheresis*
Lithium Lithium Carbamazepine Amanita phalloides
Ethylene glycol Valproic acid Paraquat
Methanol Metformin Theophylline
Salicylates Theophylline
Valproic acid
Metformin
Theophylline
*Other extracorporeal therapies.
(CRRT: continuous renal replacement therapy)
38 Section 1  Renal Replacement Therapy

■ Toxins: Toxins, which are hydrophilic and nonprotein bound, are removed by dialysis.3
■ Sepsis is one of the major causes of AKI and CRRT, which helps in volume control,
decreasing cytokine load, and as RRT in hemodynamically unstable patients.4-6
■ Hypothermic patients are put on CRRT as last resort to achieve normothermia both in
adults and pediatric population.7
■ Hyperthermia: Core temperature >39.5°C.8
■ Hemofiltration has been used in patients with severe congestive cardiac failure (CCF) to
avoid need of ventilation in chronic cases and in emergency situations.9
■ CRRT has better outcome than PD in hyperammonical states due to inborn errors of
metabolism in pediatric population. The faster removal of metabolites and ammonia
reduction had early recovery from coma and less incidence of mental retardation.10

CONCLUSION
■ Renal indications to initiate RRT are AEIOU:
– Acidosis
– Electrolyte Imbalance, e.g. hyperkalemia
– Fluid Overload
– Uremic complications like pericarditis and encephalopathy.
■ RRT as a renal support is helpful in maintaining fluid balance, dyselectrolytemia, and
providing nutrition to the critically ill with better outcome.
■ Nonrenal indications of RRT like sepsis, toxins, and hypothermia should be considered at
time of need.
■ Pediatric population benefits with early start of RRT as indicated and peritoneal dialysis is
easier and better tolerated in this population.

REFERENCES
1. James C, Khan S, Khalid R, et al. Epidemiology of acute kidney injury in the intensive care unit.
Criti Care Res Pract. 2013;2013:479730.
2. KDIGO (2012). Kidney Disease Improving Global Outcome [KDIGO] Clinical Practice Guidelines—
AKI 2012. [online] Available from: https://kdigo.org/wp-content/uploads/2016/10/KDIGO-2012-
AKI-Guideline-English.pdf. [Last accessed October, 2019].
3. Bunchman TE, Ferris ME. Management of toxic ingestions with the use of renal replacement
therapy. Pediatr Nephrol. 2011;26(4):535-41.
4. Gulla KM, Sachdev A, Gupta D, et al. Continuous renal replacement therapy in children with
severe sepsis and multiorgan dysfunction—A pilot study on timing of initiation. Indian J Crit Care
Med. 2015;19(10):613-7.
5. Macedo E, Mehta RL. Continuous dialysis therapies: core curriculum 2016. Am J Kidney Dis.
2016;68(4):645-57.
6. Grootendorst AF, Bouman CSC, Hoeben KHN, et al. The role of continuous renal replacement
therapy in sepsis and multiorgan failure. Am J Kidney Dis. 1996;28(5):S50-7.
7. Owda A, Osama S. Hemodialysis in the management of Hypothermia. Am J Kidney Dis.
2001;38(2):E8.
8. Joannidis M, Forni LG. Clinical review: timing of renal replacement therapy. Critical Care. 2011;15(3):223.
9. Brause M, Deppe CE, Hollenbeck M, et al. Congestive heart failure as an indication for continuous
renal replacement therapy. Kidney Int Suppl. 1999;56(72):S95-8.
10. Cho H. Renal replacement therapy in neonates with an inborn error of metabolism. Korean J
Pediatr. 2019;62(2):43-7.
CHAPTER 7
Initiation of Renal Replacement Therapy in
Intensive Care Unit
Ashish Nandwani, Vijay Kher

INTRODUCTION
The occurrence of acute kidney injury (AKI) is a common problem in intensive care units
(ICUs). Rapid deterioration in renal functions occurs in various clinical settings due to multiple
factors. Clinically, these may manifest as mild rise in serum creatinine to oligoanuric state
requiring renal replacement therapy (RRT). The reported incidence of AKI is approximately
9–30% in patients admitted with various medical and surgical conditions in critical care setting.
In this subgroup of patients with AKI, approximately 5% require RRT. The mortality remains
high in these patients, especially requiring RRT.1

CAUSES OF ACUTE KIDNEY INJURY IN ICU


The causes of AKI in ICU are multifactorial. Volume depletion/hypovolemia, low cardiac
output, and systemic vasodilatation are the main contributory factors. Ischemia and
nephrotoxic drugs cause AKI by acute tubular necrosis. These are complicated by cardiac and
hepatic dysfunction. Sepsis is leading cause of AKI in ICU setting, triggering a series of events
leading to shock and acute kidney injury. Drugs and contrast agents contribute to severity of
disease.2,3

MANAGEMENT OF PATIENTS WITH ACUTE KIDNEY INJURY


It is important to recognize the patients at risk of developing AKI and take preventive measures
at appropriate time, as there are no specific treatments available for reversing the AKI. It is
important to determine the basic disease and associated multiorgan dysfunction syndrome to
start an appropriate therapy.
General measures:
■ Ensure the volume status of patient along with perfusion pressures and monitor the mean
arterial pressure.
■ Hemodynamic monitoring for appropriate fluid and inotropic support.
■ Avoid the nephrotoxic drugs and modify the drug dose according to the renal function.
40 Section 1  Renal Replacement Therapy

■ Avoid nephrotoxic radiocontrast agents, if possible.


■ Avoid hyperglycemia.
■ Monitor urine output and kidney functions regularly.
Specific measures:
■ Evaluation for the underlying cause leading to renal dysfunction.
■ Institute RRT as indicated.

Renal Replacement Therapy


The most important questions for a nephrologist in a patient with severe AKI are:
■ Whether or not to start the RRT?
■ When to start the RRT?
■ Which modality is best suitable for a given patient?

Aims of Renal Replacement Therapy


The aim of RRT in critically ill patients with AKI with metabolic complications is to support
the native renal function, and thus controlling electrolyte and acid–base imbalance, as well as
to avoid fluid overload. Also, this reduces the effects of uremic toxins on nonrenal organs. The
dose of RRT has to be adjusted according to renal functions, electrolytes, nutritional needs,
and cumulative fluid balance according to the catabolic needs of the patient.
The long-term goals of RRT in a patient with AKI are patient survival and recovery of renal
functions. Whether any specific modality of RRT facilitates renal recovery and patient survival
is not known.4

Indications for Renal Replacement Therapy in Critically Ill Patients with AKI5,6
Life-threatening indications: RRT should be started emergently in presence of life-threatening
changes in electrolytes, acid–base balance, and fluid overload that are unresponsive to medical
therapies. These include:
■ Acidosis: Metabolic acidosis secondary to AKI with pH < 7.1
■ Hyperkalemia: Serum potassium > 6 mEq/L and ECG changes or heart blocks
■ Pulmonary edema: Not responsive to diuretics or to prevent the need for ventilator support
■ Uremic complications: Uremic encephalopathy, pericarditis, and neuropathy
■ Other metabolic complications: Dysnatremia, hypermagnesemia (>4 mmol/L) with anuria,
or areflexia.

Nonemergent indications: RRT should be considered in cases where fluid and metabolic
demands exceed total renal capacity. These include:
■ Solute control: There are no universally accepted levels of urea or creatinine to suggest the
start of RRT as these vary with the volume status and catabolic rate
■ Fluid removal: In oliguric/anuric patients to prevent fluid overload
■ Nutritional support: Patients requiring parenteral nutritional support
■ Ultrafiltration in patients with cardiorenal syndrome, who are nonresponsive to diuretics
■ Newer areas of interest are incorporating RRT for drug delivery and cytokine removal in
patients with septic shock.
Chapter 7  Initiation of Renal Replacement Therapy in Intensive Care Unit 41

Renal Replacement Therapy for Overdose with Dialyzable Drug7


Renal replacement therapy can be used to remove water-soluble drugs from circulation in case
of overdose. The drugs, which are not protein bound, can be removed by dialysis. Hemodialysis
can be used for drug toxicity caused by:
■ Lithium
■ Salicylate
■ Ethylene glycol
■ Methanol
■ Barbiturates
■ Cephalosporin/penicillin.

Inborn Errors of Metabolism8


Inborn errors of metabolism, especially, which are associated with hyperammonemia, need
urgent management. These require RRT support along with medical management. Continuous
RRT may be the most effective form of RRT for these disorders, as this may prevent ammonia
rebound.

Cytokine Removal in Patients with Septic Shock9


Various adsorptive filters can be used with RRT for removal of cytokines in patients with septic
shock. Cytokine and endotoxin reduction by hemoadsorption reduce the systemic levels of
pro-inflammatory and anti-inflammatory mediators, released by inflammatory cells in the
early phase of sepsis, thus reducing the cytokine levels and improving the hemodynamic
status of the patient.

Timing of Renal Replacement Therapy


The timing of RRT in critically ill patients with AKI is a subject of debate. Whether early
institution of RRT improves the outcome in patients with AKI is controversial. Few randomized
controlled trials (RCTs) have been done in this regard in last few years. Critically ill patients with
AKI, requiring mechanical ventilation, inotropic support, or both but not having potentially
life-threatening complication directly related to renal dysfunction, were subjected to either
an early or a delayed start of RRT. With the early strategy, RRT was started immediately
after randomization. With the delayed strategy, RRT was initiated only in setting of—severe
hyperkalemia, metabolic acidosis, pulmonary edema, or oliguria for more than 72 hours
after randomization. In two studies, 36% and 50% of the critically ill patients admitted in ICU,
assigned to late RRT, had spontaneous recovery of renal functions without ever receiving
RRT.10,11 Also, there was no significant difference with regard to 60-day mortality between
an early and a delayed strategy for the initiation of RRT. The need for RRT was averted in an
appreciable number of patients in delayed strategy group.
In a recent trial in patients with septic shock with severe AKI, overall mortality at 90
days was similar among patients who were assigned to an early strategy for the initiation of RRT
and those who were assigned to a delayed strategy.12 As there is no significant improvement in
patient outcomes by early initiation of RRT, the need of initiating RRT should be guided by the
presence of life-threatening emergent conditions.
42 Section 1  Renal Replacement Therapy

Modality of Renal Replacement Therapy in ICU


There are different modalities for RRT, which can be classified into either intermittent or
continuous depending upon the duration of therapy. The choice of particular modality is
primarily dependent upon patients age and size, whether vascular access is available or
not, availability of modality, local expertise, and patient hemodynamic status. Comparison
between various dialysis modalities has been shown in Table 1. Current modalities include:
■ Intermittent hemodialysis (IHD)
■ Continuous renal replacement therapy (CRRT):
– Continuous venovenous hemofiltration (CVVH)
– Continuous venovenous hemodialysis (CVVHD)
– Continuous venovenous hemodiafiltration (CVVHDF)
– Continuous arteriovenous hemofiltration (CAVH)
– Continuous arteriovenous hemodialysis (CAVHD)
– continuous arteriovenous hemodiafiltration (CAVHDF)
– Slow continuous ultrafiltration (SCUF).

Table 1: Comparison between various dialysis modalities.


Modality Advantages Disadvantages
IHD • Rapid removal of the uremic toxins • Hypotension with ultrafiltration
• Allows for “down time” for various therapeutic • Dialysis disequilibrium syndrome with
and diagnostic procedures risk of cerebral edema with rapid solute
• Reduced exposure to anticoagulation drugs removal
• Lower costs of the therapy

CRRT • In hemodynamically unstable patient • Slower clearance of uremic toxins


• Continuous removal of toxins • Need for prolonged anticoagulation to
• Easy control of fluid balance in critically ill prevent clotting
patients • Patient immobilization
• No therapy-induced increase of intracranial • Hypothermia
pressure • Increased costs
SLED • In hemodynamically unstable patient Slower clearance of uremic toxins
• Slower volume and solute removal
• Allows for “down time” for various procedures
• Reduced exposure to anticoagulation drugs
PD • Technically simple procedure • Poor clearance of solute in hypercatabolic
• Hemodynamic stability patients
• No anticoagulation required • Protein loss is more
• No need for vascular access • No control of rate of fluid removal in given
• Lower cost time
• Gradual removal of toxins • Risk of peritonitis, if prolonged
• Hyperglycemia
• Requires intact peritoneal cavity
• Impairs diaphragmatic movements
decreasing vital capacity
(CRRT: continuous renal replacement therapy; IHD: intermittent hemodialysis; PD: peritoneal dialysis; SLED:
sustained low-efficiency dialysis)
Chapter 7  Initiation of Renal Replacement Therapy in Intensive Care Unit 43
■ Hybrid therapies:
– Sustained low-efficiency dialysis (SLED)
■ Peritoneal dialysis (PD).
Which modality is better—IHD versus CRRT versus SLED?
Several RCTs have evaluated IHD to CRRT in AKI patients. Cochrane meta-analysis included
15 RCTs in 1,550 AKI patients. This meta-analysis concluded that outcomes were similar in
critically ill AKI patients treated with CRRT and IHD for hospital mortality, ICU mortality,
length of hospitalization, and renal recovery (free of dialysis on discharge) in survivors.13
However, in patients who received CRRT, the mean arterial pressure was significantly higher at
the end of the treatment, and the patients who required escalation of vasopressor therapy was
significantly lower with CRRT.
Kidney Disease Improving Global Outcomes (KDIGO) has suggested the use of CRRT
rather than standard IHD for hemodynamically unstable patients on inotropic support.5 Also,
it has been suggested by KDIGO guidelines to use CRRT rather than IHD for AKI patients with
cerebral edema or increased intracranial pressure. IHD may be associated with worsening
of neurological status by either causing hypotension causing decreased cerebral perfusion
or by dialysis disequilibrium due to rapid removal of solutes, leading to intracellular fluid
shift and causing cerebral edema. Both of these complications of hypotension and dialysis
disequilibrium can be minimized by CRRT compared to IHD.14,15
Sustained low-efficiency dialysis is another form of RRT, which can be used as an
alternative to CRRT in hemodynamically unstable patients requiring inotropes. Data on the
comparative efficacy of CRRT and SLED is limited. In a retrospective analysis of mortality data
from AKI patients requiring RRT from Australia, New Zealand, and Italy found no change in
the mortality rate by switching from CRRT to SLED in critically ill patients.16 In another cohort
of patients with AKI requiring RRT, hemodynamic instability and session interruption was
comparable in patients on SLED and CRRT.17 Hence, it is suggested to use CRRT or SLED in
hemodynamically unstable patients, depending upon the availability, local expertise, and cost
issues. Once patient becomes hemodynamically stable, should be switched to intermittent
hemodialysis.
Intermittent hemodialysis is the preferred mode of dialysis in situations where rapid
removal of solutes is required, such as severe hyperkalemia causing arrhythmia, poisoning,
and tumor lysis syndrome.6
Continuous renal replacement therapy is preferred for patients who may not tolerate
rapid shifts in fluid balance, especially with severe hemodynamic instability and on multiple
inotropes.6
Continuous renal replacement therapy or PD is preferred over IHD in patients with raised
intracranial hypertension and/or acute brain injury.6
Continuous renal replacement therapy, IHD, or SLED is preferred in patients with high-
catabolic state rather than PD.6
In children, the choice of the modality for dialysis is predominantly based on child’s age,
hemodynamic status, local expertise and experience with the RRT modality, and cost of
therapy.6
44 Section 1  Renal Replacement Therapy

What should be the dose of renal replacement therapy?


The prescribed RRT dose should be able to achieve the desired goals of fluid, solute, electrolyte,
and acid–base balance according to the patient’s catabolic requirements. Repeated assessment
is required to know the delivered dose and adjustment in prescription for further treatments.
The adequacy of the delivered dose of IHD is usually quantified by the urea reduction ratio and
Kt/V (K—urea clearance of dialyzer; t—treatment time; and V—volume of distribution of urea).
As critically ill patients are metabolically unstable and serum urea being influenced by various
factors, it is better to calculate Kt/V to assess the delivered dose of dialysis in these patients.
The KDIGO recommends thrice weekly Kt/V of 1.3 or a weekly Kt/V of 3.9 (assuming thrice
weekly treatment).5 There are two RCTs comparing the RRT dose in AKI patients. For CRRT, it is
recommended to deliver an effluent volume of 20–25 mL/kg/h in patients with AKI. However,
this dose should be dynamic and need adaptation according to the metabolic and catabolic
demands of the patient. As the clinical status of patient changes in terms of renal recovery and
increase in urine output, RRT prescription will need significant changes.6 Multicenter trials
found no benefits of increasing dose of CRRT in AKI patients above effluent flows of 20–25
mL/kg/h. The Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network
(ARFTN) Study compared standard-intensity predilution CVVHDF with a prescribed effluent
flow of 20 mL/kg/h to high-intensity CVVHDF at 35 mL/kg/h. The two study arms did not show
any differences in outcomes.18
The Hannover Dialysis Outcome Study was a prospective randomized parallel group study
in patients with AKI requiring RRT. Patients were randomly assigned to receive standard dialysis
(dosed to maintain plasma urea levels between 120 mg/dL and 150 mg/dL) or intensified
dialysis (dosed to maintain plasma urea levels <90 mg/dL). There was no differences between
intensified and standard treatment groups for survival by Day 14 (70.4% vs 70.7%) or Day 28
(55.6% vs 61.3%), or for renal recovery among the survivors by Day 28 (60.0% vs 63.0%).19
The Randomized Evaluation of Normal versus Augmented Level of RRT in ICU (RENAL)
was a multicenter study conducted in 35 centers in Australia and New Zealand. It compared
the effects of postdilution CVVHDF at doses of 25 mL/kg/h and 40 mL/kg/h on 28-day and
90-day mortality rates in 1,464 ICU patients with AKI. As in the previous studies, there was
no difference in 28-day or 90-day mortality between the two groups. The complication rate
was similar in two groups apart from hypophosphatemia, which was higher in the high-dose
group.20

Drug Dosing in Patients on Renal Replacement Therapy


For patients who receive RRT, monitor drug levels when possible and adjust drug doses
accordingly. The factors that need to be considered when dosing patients on RRT are:
■ The drug being used—molecular weight, protein binding, volume of distribution, water
and lipid solubility, renal clearance, and steric hindrance
■ Type of RRT—blood and dialysate flows, type of membrane, and pre- or postdilution
replacement fluid
■ Patient status—residual renal function.
Chapter 7  Initiation of Renal Replacement Therapy in Intensive Care Unit 45

Complications of Renal Replacement Therapy


■ Complications related to vascular access
■ Hypotension
■ Dialysis disequilibrium syndrome
■ Electrolyte imbalance
■ Hypersensitivity reactions to dialyzer membrane
■ Complications related to anticoagulation
■ Blood loss
■ Air embolism
■ Hypothermia
■ Release of pyrogens.

Use of Peritoneal Dialysis in AKI


In the recent times, there is substantial decrease in the use of PD for RRT in AKI patients because
of the availability of IHD and CRRT. The use of PD is mainly confined to the low resource setting
and in pediatrics because of the low cost and ease of administration. The indications of PD
include hemodynamic instability, difficulty in obtaining vascular access, and coagulopathy.
The potential contraindications of PD are hypercatabolic state, severe respiratory failure, severe
ileus, recent abdominal surgery, and peritoneal–pleural connections. The most important
complication related to acute PD is peritonitis.21

CONCLUSION
To conclude, patients with AKI in ICU settings requiring RRT have high morbidity and
mortality. The choice of different modalities depends upon the hemodynamic instability,
therapies available, local expertise, and indications for the RRT. In spite of adequate RRT, the
mortality remains high in this subset of patients.

REFERENCES
1. Thakar CV, Christianson A, Freyberg R, et al. Incidence and outcomes of acute kidney injury in
intensive care units: a Veterans Administration study. Crit Care Med. 2009;37(9):2552-8.
2. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational,
multicenter study. JAMA. 2005;294(7):813-8.
3. Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure—definition, outcome measures, animal
models, and fluid therapy and information technology needs: the Second International Consensus
Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8(4):R204-12.
4. Chawla LS, Bellomo R, Bihorac A, et al. Acute kidney disease and renal recovery: guideline report
of the Acute Disease Quality Initiative (ADQI) 16 Workgroup. Nat Rev Nephrol. 2017;13(4):241-57.
5. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO
Clinical Practice Guideline for Acute Kidney Injury. Kidney Int. 2012;2(1):1-138.
6. Annigeri RA, Ostermann M, Tolwani A, et al. Renal support for acute kidney injury in the
developing World. For the Acute Dialysis Quality Initiative (ADQI) Consensus Group. Kidney Int
Rep. 2017;2(4):559-78.
46 Section 1  Renal Replacement Therapy

7. Bunchman TE, Ferris ME. Management of toxic ingestions with the use of renal replacement
therapy. Pediatr Nephrol. 2011;26(4):535-41.
8. Bunchman TE, Barletta GM, Winters JW, et al. Phenylacetate and benzoate clearance in a
hyperammonemic infant on sequential hemodialysis and hemofiltration. Pediatr Nephrol.
2007;22(7):1062-5.
9. Cole L, Bellomo R, Journois D, et al. High volume hemofiltration in human septic shock. Intensive
Care Med. 2001:27(6);978-86.
10. Gaudry S, Hajage D, Schortgen F, et al. Initiation strategies for renal-replacement therapy in the
intensive care unit. N Engl J Med. 2016;375:122-33.
11. Wald R, Adhikari NK, Smith OM, et al. Comparison of standard and accelerated initiation of renal
replacement therapy in acute kidney injury. Kidney Int. 2015;88(4):897-904.
12. Barbar SD, Clere-jehl R, Bourredjem A, et al. Timing of renal-replacement therapy in patients with
acute kidney injury and sepsis. For the IDEAL-ICU trial investigators and the CRICS TRIGGERSEP
network. N Engl J Med. 2018;379(15):1431-42.
13. Rabindranath K, Adams J, Macleod AM, et al. Intermittent versus continuous renal replacement
therapy for acute renal failure in adults. Cochrane Database Syst Rev. 2007;18(3):CD003773.
14. Ronco C, Bellomo R, Brendolan A. Brain density changes during renal replacement in critically
ill patients with acute renal failure. Continuous haemofiltration versus intermittent hemodialysis.
J Nephrol. 1999;12(3):173-8.
15. Davenport A. Continuous renal replacement therapies in patients with acute neurological injury.
Semin Dial. 2009;22(2):165-8.
16. Marshall MR, Creamer JM, Foster M, et al. Mortality rate comparison after switching from
continuous to prolonged intermittent renal replacement for acute kidney injury in three intensive
care units from different countries. Nephrol Dial Transplant. 2011;26(7):2169-75.
17. Fieghen HE, Friedrich JO, Burns KE, et al. The hemodynamic tolerability and feasibility of sustained
low efficiency dialysis in the management of critically ill patients with acute kidney injury. BMC
Nephrol. 2010;11:32.
18. Palevsky PM, Zhang JH, O’Connor TZ, et al. Intensity of renal support in critically ill patients with
acute kidney injury. N Engl J Med. 2008;359(1):7-20.
19. Faulhaber-Walter R, Hafer C, Jahr N, et al. The Hannover Dialysis Outcome study: comparison of
standard versus intensified extended dialysis for treatment of patients with acute kidney injury in
the intensive care unit. Nephrol Dial Transplant. 2009;24(7):2179-86.
20. Bellomo R, Cass A, Cole L, et al. Intensity of continuous renal-replacement therapy in critically ill
patients. N Engl J Med. 2009;361(17):1627-38.
21. Chionh CY, Soni SS, Finkelstein FO, et al. Use of peritoneal dialysis in AKI: a systematic review.
Clin J Am Soc Nephrol. 2013;8(10):1649-60.
CHAPTER 8
Slow Low-efficiency Daily Dialysis in ICU
Joyita Bharati, Raja Ramachandran, Vivekanand Jha

INTRODUCTION
Sustained (or slow) low-efficiency dialysis (SLED) is an intermittent “hybrid” modality of
renal replacement therapy (RRT); with features of both continuous renal replacement therapy
(CRRT) and conventional intermittent hemodialysis (IHD). SLED therapy, first described
in 1988, utilizes a traditional IHD machine to perform dialysis for extended periods using
slower blood flow and dialysate flow rates. The primary method of solute clearance in SLED
is diffusion. However, a combination of hemofiltration (SLED-f ) adds convective solute
clearance (for better middle molecule clearance) to it. SLED has been universally accepted as
a modality of RRT in critically ill intensive care unit (ICU) patients, representing 50–100% of
RRT in Australia, New Zealand, and Italy.1

SALIENT FEATURES OF SLED


■ Dialysis duration of 6–12 hours
■ Blood flow rates (Qb) of 200–300 mL/min
■ Dialysate flow rates (Qd) of 100–300 mL/min
■ Dialysate made from mixing prepackaged electrolytes with sterile water or online
generation
■ Uses conventional IHD machines.

ADVANTAGES OF SLED
Conventional intermittent hemodialysis is associated with complications such as hemo-
dynamic instability, rapid shift and fluctuations in solutes, and the acid–base balance owing
to the relatively short and episodic periods of the therapy. Intradialytic hypotension is caused
by rapid ultrafiltration rate, which exceeds the plasma refilling rate.2 Furthermore, acute
kidney injury (AKI) in critically sick patients is often complicated by hypotension, acid–base
imbalance, and electrolyte disturbance. However, fluid removal is required in patients with
volume overload. Continuous and slower modality of RRT (CRRT) has been the solution to these
issues in the ICUs. The continuous nature of CRRT makes the effect of compartmentalization
of solutes minimal, making the patient’s urea level approach a steady state.
48 Section 1  Renal Replacement Therapy

Nevertheless, CRRT is hurdled by the requirements of the expensive machine,


solutions, need for anticoagulation/prolonged exposure to anticoagulant, and trained staff.
Modifications3-5 in the technique of IHD to optimize hemodynamic stability has led to similar
outcome6 in critically sick patients receiving IRRT and CRRT. SLED utilizes the desirable
theoretical advantages of both CRRTs, i.e.:
■ Improved hemodynamic stability
■ High-solute clearances
■ Flexible scheduling
■ Lesser need for anticoagulation
■ Less expensive equipment.

DISADVANTAGES OF SLED
■ Requirement of specifically trained nurses/staffs
■ Requirement of water treatment plants to supply pure water for dialysate preparation
■ Intermittent nature of SLED leading to solute dysequilibrium may not be ideal for an
unstable patient
■ Can worsen cerebral edema.
The widespread availability of hemodialysis machine (along with a skilled set of personnel)
in hospitals providing maintenance hemodialysis makes the first two mentioned disadvantages
less likely, even in the ICU settings.
Conditions where use of SLED is not appropriate:
■ Neurotrauma with raised intracranial pressure
■ Acute liver failure with cerebral edema/raised intracranial pressure
■ Hemodynamic instability or cardiac arrhythmias associated with high-dose inotropic/
vasopressor agents during SLED.

COMPARISON OF VARIOUS RRT MODALITIES USED FOR


CRITICALLY SICK PATIENTS
Selection of the optimal RRT modality should include both patient-specific characteristics and
ICU-specific characteristics. Patient-specific components include comorbidities, multiorgan
failure, sepsis, liver disease, increased intracranial pressure, etc. ICU-specific features include
availability of resources and expertise of the medical staff in managing patients on different
modalities of RRT. The comparison of various modalities of RRT usually administered to a
critically sick patient is given in Table 1.

WAYS TO MAKE SLED MORE EFFECTIVE IN MEETING ULTRAFILTRATION GOALS


■ Increasing frequency to daily dialysis5 (improves ultrafiltration tolerance, however, as
compared to thrice weekly IHD, six times per week SLED has not been shown to affect
mortality or renal recovery by day 60)11
■ Priming the extracorporeal circuit with 0.9% normal saline, instead of patient’s blood:3
This will reduce the relative hypovolemia during the start of therapy and allow hustle-free
ultrafiltration.
Chapter 8  Slow Low-efficiency Daily Dialysis in ICU 49

Table 1: Comparison of salient features of different renal replacement therapy (RRT) modalities for the
critically sick.
Parameter IHD SLED CRRT
Blood flow (mL/min) 7
250–400 100–300 100–200
Dialysate flow (mL/min)7 500–800 100–300 0–50
Urea clearance rate (mL/min)7 150–180 90–140 20–45
Hemodynamic tolerability 8,9
− ++ ++
Solute transport Diffusion Diffusion and/or Diffusion and/or
convection convection
Small solute clearance ++ ++ + (++)
Middle and large solute clearance + + (++) +++
Effect on intracranial pressure 7
+ + −
Nutritional support7 − − +
Need for anticoagulation7 Not mandatory Not mandatory Mandatory
Patient mobilization 7
+ + −
Short-term mortality6 = = =
Cost of therapy10 = = Higher
Note: (+) denotes advantage; (−) denotes disadvantage; (=) denotes equivocal.
(IDH: intermittent hemodialysis; SLED: slow low efficiency dialysis; CRRT: continuous renal replacement therapy)

■ Reducing the dialysate temperature:3 Decreasing the dialysate temperature (to <37°C) leads
to vasoconstriction and lesser rates of hypotension.
■ Reducing the dialysate flow (decreases rapid shifts in plasma osmolality and, hence, fluid
shifts).
■ Sodium profiling:3 Gradual increase of the dialysate sodium to 145 mmol/L would allow a
gradual increase in extravascular to intravascular fluid shift.

Technique
Machine
■ Fresenius 4008H ArRT Plus (minimum Qd allowed is 300 mL/min)
■ Fresenius 5008S (minimum Qd allowed is 100 mL/min)
■ Gambro 200S Ultra (minimum Qd allowed is 300 mL/min).

Vascular Access
■ Usually a central venous dialysis catheter
■ Arteriovenous fistula or graft (needle dislodgement during prolonged therapy needs to be
monitored).

PRESCRIPTION
The prescription for intermittent RRT is targeted for small-solute removal (clearance)
and fluid removal (ultrafiltration); it varies widely between different institutions/centers.
Clearance depends on the blood flow rate (Qb) and more so on the dialysate flow rate (Qd).
50 Section 1  Renal Replacement Therapy

The molecular weight of the solutes, dialyzer membrane, and size are other determinants of
solute clearance. Qb is dependent on vascular access function, and Qd is based on machine
characteristics for SLED, which is usually kept low owing to the significant need for dialysate
preparation for longer sessions in SLED. There is a linear relation between clearance and
ultrafiltration during diffusion till the Qd does not exceed one-third of the Qb. When the Qd/
Qb ratio exceeds 0.3, the dialysate will no longer be entirely saturated by solutes diffusing
from the blood compartment, probably decreasing the actual delivered than the prescribed
dose.12 Numerous studies have used Qb between 100 mL/min and 300 ml/min. For clinical
practice, Qd of 100 mL/min is prescribed for dialysis duration of 10–12 hours and 300 mL/min
for 6–8 hours typically (Table 2).
For adults:
■ Blood flow rate: 100–300 mL/min
■ Dialysate flow rate: 100–300 mL/min (adjusted according to machine requirements and
patient’s ultrafiltration tolerance)
■ Ultrafiltration rate: The fluid removal goal (based on patients’ intake and loss status) should
be planned over 2–3 days, rather than targeting all in the first session itself. Ultrafiltration
rate of 350 mL/hour is a safe option
■ Duration: 6–12 hours/day (dialysis adequacy of 12 hours of SLED was found to be equivalent
to 23 hours of CRRT)8
■ Frequency: 3–7 times/week
■ Anticoagulation: Not mandatory.

Table 2: Algorithm for prescription of sustained low-efficiency dialysis.


Clinical parameter Dialysis parameter Prescription
Hemodynamic Blood flow rate 100–300 mL/min (variable practice across centers)
parameters
Dialysate flow rate 100–300 mL/min (variable practice across centers)
Fluid balance Ultrafiltration 1,000–4,000 mL/over 6–12 hours; close monitoring (to
maintain mean arterial pressure >60 mm Hg; central venous
pressure about 8–10 cm H2O); increase/introduction of
vasopressor dosing as and when needed
Electrolyte imbalance Dialysate composition In case of hyperkalemia, use potassium-free dialysate; in
case of hyponatremia, use lower sodium (with minimum
gradient), in case of hypernatremia, use higher sodium
(with maximum gradient)
Acid–base imbalance Dialysate buffer Bicarbonate buffered solutions are preferred, especially in
liver failure and lactic acidosis
Bleeding diathesis Anticoagulation If present, saline flushes 100 mL/hour or as and when
(heparin-free)
If no bleeding diathesis, heparin infusion
Body surface area Dialyzer size Based on body surface area: F6 (1.3 m2), F60S/60 (1.3 m2), F7
(1.6 m2), F8 (1.8 m2), F3 (0.4 m2), F4 (0.7 m2), F5 (1 m2); high
flux dialyzer is preferred over low flux dialyzer
Chapter 8  Slow Low-efficiency Daily Dialysis in ICU 51
Heparin bolus 2,000–4,000 units followed by 500–1,000 units/hour infusion with activated
partial thromboplastin time goal of 1.5 times baseline or activated whole blood clotting time
(ACT) goal of 150–200 seconds.
■ Dialysate composition (variable): Bicarbonate based
■ Sodium: 135–145 mEq/L
■ Potassium: 2–4 mEq/L
■ Calcium: 1.25–1.75 mEq/L
■ Bicarbonate: 28–36 mEq/L.
For children:
■ Blood flow rate: 3–5 mL/kg/min
■ Dialysate flow rate: 100–300 mL/min
■ Duration: 6–12 hours/day
■ Frequency: 3–7 times/week
■ Anticoagulation: Heparin/saline.

Dialysis Dose/Adequacy (Solute Removal)


The recommendation for intermittent dialysis adequacy, in the form of Kt/V [clearance of solute
(urea) (K) multiplied by time (t) divided by volume of distribution of solute (V)], for patients
with AKI is 3.9 per week (>1 per treatment).2 Urea reduction rate (URR) has also been used to
quantify dialysis dose in patients with AKI, with a finding of survival benefit with a URR > 58%
per treatment.13 URR was found to be 52 ± 3% in patients undergoing extended daily dialysis
of an average 11.7 ± 0.1 hour in a study comparing continuous venovenous hemofiltration
and extended daily dialysis; with similar URR in the two groups.8 Equivalent renal clearance
(EKRc) is another parameter used to define solute removal adequacy. On comparing SLED-f
(8 hours duration; 6 days a week) with CRRT in critically ill patients with AKI, weekly Kt/V
was found to be significantly higher in the SLED group and EKRc was found to be similar in
the two groups.14 Furthermore, Kt/V (urea) achieved with SLED using Qd of 100 mL/min and
Qb of 200 mL/min for a duration of 12 hours was between 1.2 and 1.4, similar to conventional
IHD.4 The dialysate flow rate (Qd) used in this study14 was 350 mL/min, slightly higher than Qd
of 100–300 mL/min in standard clinical practice for SLED. Nevertheless, the observation of
equivalent solute (small solute) removal with SLED and CRRT makes the former an appealing
alternative therapy in critically ill patients with AKI. Clinical symptoms of azotemia, correction
of electrolyte imbalance, and volume control are surrogate parameters for assessing dialysis
adequacy on a day-to-day basis.

MONITORING DURING SLED


■ Hemodynamic parameters such as blood pressure, heart rate, central venous pressure,
inotrope, and vasopressor dosing
■ Fluid status including all fluid intake, sensible and insensible loss; body weight monitoring
(if possible); bedside clinical monitoring using peripheral edema, jugular venous pulsations,
heart rate, blood pressure, and inferior venocaval (IVC) collapsibility/distension; invasive
52 Section 1  Renal Replacement Therapy

monitoring such as central venous pressure and/or pulmonary capillary wedge pressure
and blood volume (machine depicted) to predict ultrafiltration tolerance.
■ Serum potassium, sodium, calcium, phosphorus, magnesium, and bicarbonate to be
checked 1–2 hours after dialysis is completed (cellular to plasma shifts in electrolytes
stabilize by 1–2 hours). About 1.5 g of phosphorus is removed during a 12-hour SLED
with Qb 200 mL/min, Qd 100 mL/min using a low flux (1.8 m2) dialyzer.4 So, intravenous
phosphorus replacement (at 0.1–0.2 mmol/kg) would be required in those receiving daily
treatment. Supplementation of protein at 0.2 g/kg/day over daily requirement is advised.
■ Coagulation parameters (aPTT or ACT, if on heparin infusion).
■ Intracranial pressure monitoring (if ICP monitoring catheter is in situ, or noninvasive
means if otherwise) in cases where SLED is used in the presence of cerebral edema/severe
intracranial trauma.
■ Blood antibiotic level to maintain therapeutic drug levels (optional).

Drug Dose Modification during SLED


The efficacy of a drug depends on the availability of the drug in the plasma. Kidneys are a major
source of drug elimination. The clearance of a drug depends on the volume of distribution
and protein binding of the drug, the patient’s residual renal function, and the modality of
RRT. Clearance per hour is higher with conventional IHD as compared to SLED or CRRT.
However, owing to the prolonged duration of SLED, clearance per day is more with SLED than
conventional IHD. Moreover, dialyzer type would affect clearance (high-flux dialyzer having
higher clearance) and rebound of drugs would occur after dialysis. Timing of administration
of the drug with respect to starting or ending of SLED and dose modification on the days on
and off SLED are critical for the best efficacy (along with limited toxicity) of the drug. Typically,
renally cleared antibiotics should be adjusted as per CRRT for a patient undergoing SLED for
6–12 hours per day. The drug dosing of the commonly administered antibiotics is detailed in
Table 3.

CRITERIA FOR STOPPING SLED


■ Hemodynamic intolerance despite vasopressor use (shifting to CRRT may be an option)
■ Improved hemodynamics (shifting to conventional IHD may be considered, if need for
RRT persists)
■ Improvement in renal function (no further requirement for RRT).

OUTCOMES
Hemodynamic Tolerance
Hemodynamic tolerability of critically ill patients with AKI during intermittent RRT is a
significant practical hurdle to adequate and safe ultrafiltration and solute removal. CRRT is one
way to curb this issue; however, the introduction of SLED has made it possible with intermittent
RRT too. The hemodynamic tolerability of SLED as compared to CRRT was found to be similar
in two cohort studies involving critically ill hypotensive patients with AKI.17,18 However, these
were limited by observational nature and assignment bias by physicians. Moreover, two small
Chapter 8  Slow Low-efficiency Daily Dialysis in ICU 53

Table 3: Antibiotic dosing in patients undergoing sustained low-efficiency dialysis (SLED)*.15,16


Drug Recommendation
Vancomycin 15–25 mg/kg initial dose followed by therapeutic drug level monitoring (trough
levels of 10–20 mg/L) at 24 hours after initial dose (to decide on supplemental
dose), usually dosed every 24–72 hours, may need more frequently if on high-flux
SLED
Meropenem 0.5–1 g every 8 hours (for high-flux SLED)
Ertapenem 1 g/day (not affected by SLED)
Colistin Loading dose of 6–9 million units and maintenance of 3 million units every
8 hours
Levofloxacin 250–500 mg every day (preferably after SLED)
Moxifloxacin 400 mg/day after SLED
Linezolid 600 mg every 12 hours (dosing at the end of SLED)
Piperacillin–Tazobactam 2.5 g every 8 hours (tailor to bacterial minimum inhibitory concentration)
Note: *Many units do not change the dose in first 48 hours.

(involving <50 patients)8,19 and one large (115 patients)20 randomized trials demonstrated safe
hemodynamic tolerance during SLED as compared to CRRT in critically ill patients in the ICU.
The mean arterial pressure (MAP) was noted to decrease after the first 2 hours of starting RRT
in SLED-f group as compared to CRRT. However, there were no differences in heart rate and
vasopressor dose between the groups.19 The effectiveness and good hemodynamic tolerability
noted in these reports make SLED a promising modality of RRT in the ICUs.

Mortality
The mortality of patients undergoing SLED was not shown to be increased as compared to the
predicted mortality rate based on severity of illness scores.4 Among patients in a surgical ICU,
SLED (12 hours) and CRRT (24 hours) groups were found to have similar 90-day mortality and
hemodynamic stability with lower costs and nursing time in the SLED group.19 Another study
on critically ill patients found similar mortality rates between SLED and CRRT groups.21 The
Stuivenberg Hospital Acute Renal Failure (SHARF) study did not show mortality difference,
both short-term and long-term at 1 and 2 years, between patients given intermittent RRT and
CRRT.22 The VA/NIH Acute Renal Failure Trial Network (ATN) study reported no difference in
the mortality between intensive RRT (including IHD, SLED, and CRRT) and less intense RRT,
although the number of treatments with SLED comprised of <5% of the total treatments given.23
So, short-term mortality in critically ill patients has not been shown to vary with different RRT
modalities.

Renal Recovery
Renal recovery is usually defined as persistent nonrequirement of dialysis, although the
definitions are variable. In a systematic review and meta-analysis on patients with AKI in the
ICU, the overall proportion of renal recovery and the time to renal recovery were found to be
similar in both SLED and CRRT.24
54 Section 1  Renal Replacement Therapy

TAKE HOME MESSAGES


■ SLED is a “hybrid” RRT combining features of continuous and intermittent RRT.
■ Ease of operation, widespread availability, and the lower cost make it an appealing
alternative to CRRT in critically ill patients with hemodynamic instability.
■ Patients requiring frequent mobilization for diagnostic or therapeutic purposes and/or
with contraindication to anticoagulants specifically benefit from SLED.
■ Outcomes such as hemodynamic tolerance, renal recovery, and mortality have been
reported to be similar in SLED and CRRT modalities.

REFERENCES
1. Marshall MR. Prolonged Intermittent or Hybrid Renal Replacement Therapies; 14th Annual
International Conference on Continuous Renal Replacement Therapies; February 25–28, 2009;
San Diego California. Unpublished data presented.
2. Rosner MH, Ostermann M, Murugan R, et al.; ADQI XII Investigators Group. Indications and
management of mechanical fluid removal in critical illness. Br J Anaesth. 2014;113(5):764-71.
3. Schortgen F, Soubrier N, Delclaux C, et al. Hemodynamic tolerance of intermittent hemodialysis
in critically ill patients: usefulness of practice guidelines. Am J Respir Crit Care Med. 2000;162(1):
197-202.
4. Marshall MR, Golper TA, Shaver MJ, et al. Sustained low efficiency dialysis for critically ill patients
requiring renal replacement therapy. Kidney Int. 2001;60(2):777-85.
5. Schiffl H, Lang SM, Fischer R. Daily hemodialysis and the outcome of acute renal failure. N Engl
J Med. 2002;346(5):305-10.
6. Vinsonneau C, Camus C, Combes A, et al. Continuous venovenous haemodiafiltration versus
intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction
syndrome: a multicentre randomised trial. Lancet. 2006;368(9533):379-85.
7. John S, Eckardt KU. Renal replacement strategies in the ICU. Chest. 2007;132(4):1379-88.
8. Kielstein JT, Kretschmer U, Ernst T, et al. Efficacy and cardiovascular tolerability of extended
dialysis in critically ill patients: a randomized controlled study. Am J Kidney Dis. 2004;43(2):342-9.
9. Kellum JA, Mehta RL, Angus DC, et al.; ADQI Workgroup. The first international consensus
conference on continuous renal replacement therapy. Kidney Int. 2002;62(5):1855-63.
10. Manns B, Doig CJ, Lee H, et al. Cost of acute renal failure requiring dialysis in the intensive care
unit: clinical resource implications of renal recovery. Crit Care Med. 2003;31(2):449-55.
11. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO
clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2:1-138.
12. Fleming GM. Renal replacement therapy review: past, present and future. Organogenesis.
2011;7(1):2-12.
13. Paganini E, Tapolyai M, Goormastic M, et al. Establishing a dialysis therapy/patient outcome
link in intensive care unit acute dialysis for patients with acute renal failure. Am J Kidney Dis.
1996;28:S81-9.
14. Berbece A, Richardson R. Sustained low-efficiency dialysis in the ICU: cost, anticoagulation, and
solute removal. Kidney Int. 2006;70(5):963-8.
15. Sethi SK, Krishnappa V, Nangethu N, et al. Antibiotic dosing in sustained low-efficiency dialysis
in critically ill patients. Can J Kidney Health Dis. 2018;5:1-12.
16. Bogard KN, Peterson NT, Plumb TJ, et al. Antibiotic dosing during sustained low-efficiency dialysis:
Special considerations in adult critically ill patients. Crit Care Med. 2011;39(3):560-70.
17. Fieghen HE, Friedrich JO, Burns KE, et al. The hemodynamic tolerability and feasibility of sustained
low efficiency dialysis in the management of critically ill patients with acute kidney injury. BMC
Nephrol. 2010;11:32.
Chapter 8  Slow Low-efficiency Daily Dialysis in ICU 55
18. Kumar VA, Yeunn JY, Depner TA, et al. Extended daily dialysis vs. continuous hemodialysis for ICU
patients with acute renal failure: a two-year single center report. Int J Artif Organs. 2004;27(5):371-9.
19. Baldwin I, Bellomo R, Naka T, et al. A pilot randomized controlled comparison of extended
daily dialysis with filtration and continuous veno-venous hemofiltration: fluid removal and
hemodynamics. Int J Artif Organs. 2007;30(12):1083-9.
20. Schwenger V, Weigand MA, Hoffmann O, et al. Sustained low efficiency dialysis using a single-
pass batch system in acute kidney injury-a randomized interventional trial: the renal replacement
therapy study in intensive care unit patients. Crit Care. 2012;16(4):R140.
21. Cheng J, Hu S, Lu H, et al. Comparison of the therapeutic effectiveness of sustained low-efficiency
dialysis (SLED) with continuous blood purification (CBP) in critically ill patients. Cell Biochem
Biophys. 2013;67(3):923-7.
22. Lins RL, Elseviers MM, Patricia VN, et al. Intermittent versus continuous renal replacement therapy
for acute kidney injury patients admitted to the intensive care unit: results of a randomized clinical
trial. Nephrol Dial Transplant. 2009;24:512-8.
23. VA/NIH Acute Renal Failure Trial Network, Palevsky PM, Zhang JH, et al. Intensity of renal support
in critically ill patients with acute kidney injury. N Engl J Med. 2008;359(1):7-20.
24. Kovacs B, Sullivan KJ, Hiremath S, et al. Effect of sustained low efficient dialysis versus continuous
renal replacement therapy on renal recovery after acute kidney injury in the intensive care unit:
a systematic review and meta-analysis. Nephrology (Carlton). 2017;22(5):343-53.
CHAPTER 9
Continuous Renal Replacement Therapy:
Know the Machine
Simant Jha, Sameer Bhuwania, Sanjeev Saxena

INTRODUCTION
Continuous renal replacement therapy (CRRT) has been in common use in intensive care units
as a dialysis alternative in patients who are hemodynamically compromised with vasopressor
support1 along with those patients with increased intracranial pressure like after neurosurgery
or fulminant hepatic failure.2
In this chapter, we would learn about the machine (Fig. 1), its various parts, and types of
therapies which can be provided by it (Box 1).

Fig. 1: Basic outlook of the machine and its parts.


Source: Taken with permission from Gambro.Baxter.
Chapter 9  Continuous Renal Replacement Therapy: Know the Machine 57

Box 1: Therapeutic modalities provided by CRRT (continuous renal replacement therapy) machine.
Various modalities offered by CRRT machine:
• Continuous venovenous hemodialysis (CVVHD)—small solute removal
• Continuous venovenous hemofiltration (CVVHF)—fluid removal only
• Continuous venovenous hemodiafiltration (CVVHDF)—small and large fluid removal
• Slow continuous ultrafiltration (SCUF)—fluid removal only
• Therapeutic plasma exchange (TPE)

Fig. 2: The basic components of continuous renal replacement therapy (CRRT) process.
Source: Taken with permission from Gambro.Baxter.

Basic components of the CRRT system (Fig. 2) include:3


■ CRRT machine
■ Dialyzers
■ Solutions
■ Anticoagulants
■ Vascular access.

CRRT MACHINE (TABLE 1)


Many companies manufacture CRRT machine but we have had experience with the one’s
made by Baxter3 and Fresenius.4 All the machines work on the same basic principles of 230V,
50 Hz, 15A earthed supply as that in India. It consists of the following parts3 (Fig. 3):
■ Communication unit
■ Flow control unit
■ Fluid control unit.
The details of the various components are described as follows:

Communication Unit
It consists of a touchscreen panel containing the user manual and input details, through which
we can fill in the various details of therapy. Through this panel, we can set up the rate of blood
58 Section 1  Renal Replacement Therapy

Table 1: The various types of continuous renal replacement therapy (CRRT) machines available and the
description of their working.2
Machine Prismaflex Multifiltrate Multifiltrate Diapact
parameter (Baxter/Gambro) (Fresenius) (pediatric option) (B. Braun)
Electrical 100–240 V, AC, 100–240 V, 3.2 A, AC 100–240 V, 3.2 A, AC 110–240 V, 3.5 A, AC
requirement 50/60 Hz 50/60 Hz 50/60 Hz 50/60 Hz
Roller pumps 5 6 6 3
Scales 4 4 4 3
Principle Gravimetric Gravimetric Gravimetric Gravimetric
Range of load cell 0–11 kg Up to 24 kg Up to 24 kg 0–27 kg
Filter sets Dedicated Dedicated cartridges, Dedicated Dedicated but filter
but any filter/dialyzer cartridges, but any change possible with
usable. Individual filter/dialyzer usable. Luer Lock and Hansen
tubing lines can be Individual tubing connector system.
changed lines can be changed Individual tubing lines
can be changed
Blood flow rate 10–450 mL/min 10–500 mL/min 10–100 mL/min 10–500 mL/min
Dialysate flow 0–8,000 mL/hour 100–4,800 mL/hour 100–1,500 mL/hour 0–300 mL/min
rates
PBP rate 0–8,000 mL/hour — — —
Replacement fluid 0–8,000 mL/hour 100–9,600 mL/hour 100–3,000 mL/hour 0–250 mL/min
Effluent 0–8,000 mL/hour 12 liters 0–400 mL/min
Ultrafiltration rate 0–2,000 mL/hour 0–1800 mL/hour 0–500 mL/hour 0–2,000 mL/hour
Heparin 50-mL syringe 50-mL syringe 50-mL syringe 50-mL syringe
Regional citrate Possible one Possible integrated Not specified
anticoagulation external pump
required

Fig. 3: The various parts of the machine.


Source: Taken with permission from Gambro.Baxter.
Chapter 9  Continuous Renal Replacement Therapy: Know the Machine 59
flow, dialysate, replacement fluid, and anticoagulation. This panel also gives us the pressure
level at various pressure ports as well as alarms us in case of a clot in dialyzer.

Flow Control Unit


This unit contains a stator supporting the blood tubing, syringe pump for heparin infusion
along with pinch valves for pressure sensing. It has five pumps in the center of the panel and
two pressure sensors on the side, which take part in the therapy and blood flow from 0 mL/
min to 450 mL/min can be achieved. The dialysate and replacement fluid rate can be set up to
6,000 mL/min depending on the requirement. The ultrafiltration pump (UF pump) works on
flow sensor systems with volumetric control, which can vary from 0 mL/hr to 2,000 mL/hr.3
Heparin syringe pump is present separately in a vertical position (syringe volumes: 10, 20,
30, and 50 cc) with Luer Lock, and infused into the positive-pressure segment of the blood
circuit, which reduces the risk of air embolism.

Preconnected Set with Color-coded Line (Fig. 4)


It is sterile packed set, which has a barcode attached to it. This is unwrapped and put onto the
machine, which reads the barcode and accepts the tubing to fit onto it. Each machine has a
specific code, which is read before it accepts the set for functioning.

Pre-blood Infusion Set (Fig. 5)


It is a special kind of connection, so that replacement fluid can be given prefilter.

Deaeration Chamber (Fig. 6)


It is a pressure control chamber (8 mL in volume) with a spinning cylinder inside. The air
generally enters the circuit in case of a leak on the negative pressure side and presents as micro
bubbles. This chamber helps to detect it and gives an opportunity to suck out the air bubbles
from the blood compartment before it returns to the body.

Blood Leak Detector


It detects the leak of blood as low as 0.35 mL/min from the machine circuit and alarms the user.

Fig. 4: Dialyzer with preconnected tubings. This is a barcoded set, which gets attached to the machine for working.
Source: Taken with permission from Gambro.Baxter.
60 Section 1  Renal Replacement Therapy

Fig. 5: Pre-blood infusion set connected to the arterial Fig. 6: This chamber helps to separate the air in the
end of the tubing, so that pre-dilution of blood can circuit. Air being lighter floats on the top of the blood
be done. column.
Source: Taken with permission from Gambro.Baxter. Source: Taken with permission from Gambro.Baxter.

Arterial Pressure Monitor


It measures the pressure gradient between the blood flow access and the blood pump using
a strain gauge sensor. This is a negative pressure system and alarms in case of disconnection,
separation of blood tubing, or obstruction in the blood circuit.

Venous Pressure Monitor


It is between the blood pump and the venous needle, which returns the blood into body. This
is a positive pressure system and generally alarms when there is obstruction to the bloodline
connecting it back to the body.

Fluid Control Unit


This is the lower most part where all the fluid bags are hanged onto the side. These all are
color-coded and slide onto the bars, have a port in their lower end through which needles can
be inserted and connection to the main pump can be established. These are weight-based
measurements, which can detect low weight and sound alarm to change bags whenever
required.

DIALYZERS
Synthetic dialyzers like polysulfone, polyacrylonitrile, or polycarbonate are preferred because
of their lower immunogenicity and better solute removal (Table 2).2 Surface area up to 1.7 m2 is
chosen based on dose requirement and the body size of the patient.2 Removal of inflammatory
mediators (IL-1, IL-6, and IL-8) and larger molecular weight solutes may offer advantages in
sepsis or systemic inflammatory response syndrome.1 The basic concept of clearance during
CRRT is via diffusion and convection, irrespective of the type of dialyzer used.1
Chapter 9  Continuous Renal Replacement Therapy: Know the Machine 61

Table 2: The various types of dialyzers available for continuous renal replacement therapy (CRRT).2
Filter
specifications M100 M60 HF20 Ultraflux AV Paed
Membrane AN-69 Polyarylether Polysulfone
Polycarbonate
Surface area (m2) 1.0 0.6 0.2 0.2
Appropriate patient >30 11–29 <8 <10 kg
weight (kg)
Blood flow (mL/min) 75 and above 50 and above 20–100 No data
minimum to maximum
Set blood volume (mL) 152 93 60 54
Priming volume (mL) 66 42 24 18
Maximum TMP (mm 450 450 500 500
of Hg)
Clearance in CVVHD @Qb = 150 mL/min @Qb = 100 mL/min @Qb = 50 mL/min No data
mode with UF = 0 and effluent 2.5 L/hr and effluent 1 L/hr and effluent 0.5
L/hr
Urea (mL/min) 41 17 8.3 No data
Inulin (mL/min) 23 12 6.9 No data
(CVVHD: continuous venovenous hemodialysis; TMP: transmembrane pressure)

DIALYSATES AND REPLACEMENT SOLUTIONS


Continuous renal replacement therapy contains different types of fluids, which come premixed
as commercially prepared sterile solutions (Table 3). They are typically packaged in 5-L bags but
in some cases with two compartments that need to be mixed prior to use. Most of the patients
undergoing CRRT are in hemodynamically compromised state and bicarbonate is used as
buffer in dialysate. Lactate-buffered solutions are avoided in these cases since metabolism of
lactate to bicarbonate by the liver is impaired due to hypotension and multiorgan failure. The
KDIGO guideline5 also suggests the same in patients with acute kidney injury with circulatory
shock or liver failure and lactic acidemia.
The various kinds of solutions available in the market (Table 3):
■ Bicarbonate-based solutions: Bicarbonate-containing bags are the most commonly used
two-compartment systems. Bicarbonate is the buffer of choice (range: 25–35 mmol/L) in
them and these bags are used as both dialysate and replacement fluid.
■ Most of these commercially available fluids are potassium free in composition since almost
all of them have reduced urine output and risk of hyperkalemia, if not having persistent
hyperkalemia. Therefore, we need to add extra potassium in the bag, if the patient has low
serum levels.
■ Citrate-based solutions: These are the new generation dialysate fluids, which are
administered prefilter. When used for CRRT, the basic advantage in these fluids is that
additional anticoagulation is not required for these cases.
62 Section 1  Renal Replacement Therapy

Table 3: Composition of various kinds of dialysate and replacement fluids available.2


Composition MultiBic Multiplus Prismasol Regiocit Biphozyl
(mmol/L) (Fresenius) (Fresenius) (Gambro) (Baxter) (Baxter)
Sodium 140 140 140 140 140
Potassium 0–4 2 0 0 4
Calcium 1.5 1.5 1.75 0 0
Magnesium 0.5 0.75 1 0 0.75
Chloride 110 110 110 86 122
Bicarbonate 35 35 32 0 22
Phosphate — 1 — — 1–2
Glucose 5.55 5.55 0 0 0
Citrate — — — 18 —
Osmolality 290–300 300 287 244 290
(mOsmol/L)

■ Calcium-free solutions: When citrate-based fluids are used as prefilter, we need these fluids
as dialysate and replacement fluids, otherwise the clotting process gets reactivated.
The various other electrolytes, which are part of the fluids, are discussed here in detail. The
composition can be varied according to our requirements in the patient.
■ Sodium: Commercially prepared fluids contain physiologic sodium concentration
(140 mEq/L) and any variation with serum levels needs to be adjusted through IV lines.
■ Potassium: Commercially prepared fluids have varying levels of potassium as discussed in
the range from 0, 2, or 4 mEq/L. Extra potassium is added to the bags to correct in case of
hypokalemia.
■ Phosphate: Commercially prepared fluids do not contain phosphorus and hence
hypophosphatemia during CRRT is common and can lead to respiratory muscle weakness.
Therefore, phosphate should be replaced intravenously in these cases along with frequent
monitoring.6 Newer preparations with replacement solution containing phosphate are
available.
■ Calcium and magnesium: Commercially prepared fluids contain both these elements in
fixed combination amounts, 1.5–1.75 mM of calcium and 0.5–0.6 mM of magnesium.
■ Glucose: Commercially prepared fluids usually contain physiologic glucose concentrations,
usually 5.5 mM (100 mg/dL).1 Use of glucose-free fluids in CRRT can also be used and is
sometimes associated with hypoglycemia and adverse nutritional balance.7 There is no
written protocol for glucose control separately during hemodialysis, but regular hourly
monitoring during the therapy is required as in other critical patients.
■ Temperature of dialysis solution/replacement fluid: CRRT sets the dialysis solution and
replacement fluid at room temperature, resulting in heat subtraction from the patient
giving hemodynamic benefit. Studies in sheep show benefit of warming of blood in the
extracorporeal circuit.8
Chapter 9  Continuous Renal Replacement Therapy: Know the Machine 63

ANTICOAGULATION
Since most of the cases undergoing CRRT in ICU setup are very sick, hemodynamically
unstable and may have concomitant thrombocytopenia or impaired coagulation, giving
anticoagulation to these patients is very risky during the therapy. The protocol to use
anticoagulation in these patients is slightly different and will be discussed in detail in the
following paragraph.

Clotting Tests used to Monitor Heparin Therapy


■ Activated partial thromboplastin time (aPTT) i) is used for adjusting the unfractionated
heparin infusion rate.1
■ Activated clotting time (ACT): This test uses siliceous earth to accelerate the clotting process.
The details of these tests are beyond the scope of our discussion.
■ Heparin infusion method:1 After attachment of the primed hemofilter or dialyzer, 5,000 units
of heparin are injected into the patient via the venous bloodline. Next, a constant infusion
of heparin (500–1,000 units/hr) is started via an intravenous infusion pump. Therapy is
initiated and monitoring is done according to the protocol as discussed in Table 4.
■ Intermittent heparin bolus method: An initial bolus of 2,000–5,000 units of unfractionated
heparin followed by 1,000–2,000-unit bolus dose every 2–3 hours. aPTT levels can be
monitored and further dosing can be decided.
■ Regional citrate anticoagulation method (RCA):9 This is the most reliable method of
anticoagulation and now used at many centers in Delhi including ours. During this therapy,
citrate infusion is started as part of Regiocit solution and 1 ampule for calcium chloride
(50 mL solution with 0.9% saline) is connected to a peripheral line for continuous infusion
during the therapy. We suggest that the rates of citrate and calcium infusions should be
adjusted according to Table 5.
■ Heparin-free method: Saline solution flushes of 100–200 mL every 30 minutes helps wash
off fibrin strands from the membrane. However, membrane efficacy may be compromised
or filter half-lives may be reduced in these cases.

VASCULAR ACCESS (TABLE 6)


We recommend not using arteriovenous techniques for CRRT therapy since access flow is a
problem in these cases due to profound shock.2 Also, prolonged therapy can cause needle
dislodgement and extravasation of blood further complicating it. The right internal jugular vein
is considered for temporary access, because it allows for a more direct route to the superior

Table 4: Heparin infusion protocol.


Maintain arterial aPTT 40–45 s Maintain venous aPTT >65 s
If arterial aPTT >45 s, decrease heparin by 100 IU/hr If venous aPTT <65 s, increase heparin by 100 IU/hr, but
If arterial aPTT <40 s, increase heparin by 200 IU/hr only if arterial PTT <45 s
(aPTT: activated partial thromboplastin time)
Note: Monitoring: aPTT measured in arterial and venous blood lines every 6 hour.1
64 Section 1  Renal Replacement Therapy

Table 5: Citrate anticoagulation protocol used by us during continuous renal replacement therapy
(CRRT).
Prefilter–iCa iCa iCa
Patient iCa Increase citrate dose by 0.5 mmol/L and Increase calcium Decrease citrate dose by 0.5
increase calcium dose by 2.5 mL/hr by 2.5 mL/hr mmol/L and increase calcium
dose by 2.5 mL/hr
iCa Increase citrate dose by 0.5 mmol/L No change Decrease citrate dose by 0.5
mmol/L
iCa Increase citrate dose by 0.5 mmol/L and Decrease calcium Decrease citrate dose by 0.5
decrease calcium dose by 2.5 mL/hr dose by 2.5 mL/hr mmol/L and decrease calcium
dose by 2.5 mL/hr

(iCa: ionized calcium level)


Note: Monitor these levels 2 hourly for initial 6 hours or until the levels are in the normal range, later 6 hourly
till the completion of therapy.

Table 6: The size of various dialysis catheters used according to patient weight and age.2
Catheter site and type Right IJV Left IJV Femoral Diameter
Temporary adult catheter (tip to hub) 13–16 cm 19–20 cm 19–23 12–14 F (dual lumen)
Adult cuffed tunneled catheter 19–23 cm 27–33 cm 45–55 cm 11.5–14.5 F
(tip to cuff )
Pediatric cuffed tunneled catheters 12–15 cm 19.5 cm Variable 8–12 F
(tip to cuff )
(IJV: internal jugular vein)

vena cava as compared to the left jugular vein.2 The length of a right-sided catheter should be at
least 13.5 cm for an adult, while that of a left internal jugular cannula is 16–20 cm. It may be left
for a period up to 3 weeks since the risk for bacteremia increases later.1 Femoral veins should
be considered as the second choice for CRRT. Right subclavian cannula should be 15 cm and a
left subclavian vein cannula around 16 cm, but it is discouraged because it may lead to stenosis
of the vessel.10 The use of topical antibiotics at the skin insertion site and use of antibiotic locks
are not suggested because they may promote fungal infections and antimicrobial resistance.
The access should not be used for administering drugs or TPN or measurement of central
venous pressure.

REFERENCES
1. Daugirdas J, Blake P. Handbook of Dialysis, 5th edition. Philadelphia, PA: Lippincott Williams &
Wilkins; 2014.
2. HD draft guidelines ISN. (2019). Setting up of HD unit. [online] Available from: http://isn-india.
org/file/HD-draft-guidelines-2019-ISN.pdf. [Last accessed October, 2019].
3. Mortel M (Fascilitator). PrismaFlex CRRT learn book. 2012. (Reference taken with permission from
Baxter).
4. Fresenius Medical Care. CRRT and plasmapheresis filters. [online] Available from: https://www.
freseniusmedicalcare.asia/en/healthcare-professionals/acute-therapies/crrt-and-plasmapheresis-
filters. [Last accessed October, 2019].
Chapter 9  Continuous Renal Replacement Therapy: Know the Machine 65
5. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney International Supplements
(2012) 2, 1; doi:10.1038/kisup.2012.1
6. Demirjian S, Chertow GM, Zhang JH, et al. Model to predict mortality in critically ill adults with
acute kidney injury. Clin J Am Soc Nephrol. 2011;6(9):2114-20.
7. Takahashi A, Kubota T, Shibahara N, et al. The mechanism of hypoglycemia caused by hemodialysis.
Clin Nephrol. 2004;62(5):362-8.
8. De Block C, Van Gaal L, Rogiers P, et al. Intensive insulin therapy in the intensive care unit:
assessment by continuous glucose monitoring. Diabetes Care. 2006;29(8):1750-6.
9. Tolwani AJ, Prendergast MB, Speer RR. A practical citrate anticoagulation continuous venovenous
hemodiafiltration protocol for metabolic control and high solute clearance. Clin J Am Soc Nephrol.
2006;1(1):79-87.
10. Lobo V; Indian Society of Nephrology. (2012). Standard treatment guidelines haemodialysis.
Ministry of Health and Family Welfare, Government of India.
CHAPTER 10
Continuous Renal Replacement Therapy
Prescription in ICU
Girish V Kumthekar, Jyothsna Guttikonda, Rajasekara Chakravarthi M

WHAT IS CONTINUOUS RENAL REPLACEMENT THERAPY?


Continuous renal replacement therapy (CRRT) is a modality of renal replacement/support,
which works round the clock inducing less drastic and rapid fluid and solute shifts across body
fluid compartments in critically ill patients. CRRT nomenclature is self-explanatory and tells
us about the type of access used (AV for arteriovenous and VV for venovenous) and mode
of solute and fluid clearance [continuous venovenous hemofiltration (CVVH), continuous
venovenous hemodialysis (CVVHD), continuous venovenous hemodiafiltration (CVVHDF)]
employs diffusive clearance with no replacement fluid being used. CVVH, employing
convective clearance, has replacement fluid (pre- and/or postfilter), which gets removed by
machine as default with no dialysis fluid being used. CVVHDF has best of both worlds having
dialysate (diffusive clearance) and replacement fluid (convective clearance). Therefore, this
article would mean CVVHDF whenever we discuss CRRT.
Choosing CRRT modality is discussed in Table 1.

Table 1: Choosing continuous renal replacement therapy modality.


Mode Replacement fluid Dialysate Ultrafiltration Clearance
Continuous venovenous Yes No Yes Convective
hemofiltration (CVVH)
Continuous venovenous No Yes Yes Diffusive
hemodialysis (CVVHD)
Continuous venovenous Yes Yes Yes Convective
hemodiafiltration +
(CVVHDF) Diffusive
Slow continuous No No Yes Plasma water
ultrafiltration (SCUF) removal [solvent
drag]*
*Some solutes dragged along with water removal.
Chapter 10  Continuous Renal Replacement Therapy Prescription in ICU 67

WHY IS IT NEEDED?
Acute kidney injury (AKI) is a serious complication in critically ill patients because of high
mortality, morbidity, and economic implications. Sepsis is the leading cause of AKI in the
intensive care unit (ICU), and 45–70% of all AKI is associated with sepsis.1,2 AKI requiring
dialysis is a severe condition with a high mortality rate of 40–50%. When associated with a
distant organ dysfunction such as cardiac or respiratory failure, the mortality increases to
60–80%. CRRT is the most common therapy for septic AKI.1 The main reason for CRRT being
widely used in critically ill patients is less hemodynamic instability. Clinicians should pay
attention not only to the well-known aspects of CRRT in septic AKI, but also to other effects
such as clearance of cytokines, anticoagulant, and intervention of nutrition.3,4
Objectives for initiating CRRT are summarized in Table 2.

TOOLS NEEDED
Man
Trained staff is of paramount importance to conduct CRRT program effectively. This requires
frequent training, exchange of ideas, and priming for troubleshooting. Dialysis technicians
and nursing staff need to document frequently done laboratory checks and act accordingly.
Unit protocols need to be devised for smooth functioning and uniformity in prescribing
CRRT.

Machine
Dedicated CRRT machines are available, which are smart enough to automated priming,
sensitive alarming system, and safety measures. CRRT circuit kits with filter are compatible for
both heparin and citrate anticoagulation. Laboratory backup for testing electrolytes, arterial
blood gas (ABG), and ionized calcium is crucial, as it affects our CRRT prescriptions directly.

Money
This probably is the most important limiting factor to carry forward CRRT program. If we
consider improved filter/circuit life with newer anticoagulants and protocols, improvement
on mortality and morbidity indices with AKI, then the cost of CRRT may be actually coming
down in near future.

Table 2: Objectives for initiating continuous renal replacement therapy.


Conventional Unconventional
• Metabolic acidemia • Hyperphosphatemia
• Hyperkalemia • Hyponatremia
• Fluid overloads • Hybrid therapies (ECMO, MARS)
• Hemodynamic instability • extracorporeal immunomodulation
• Nutritional requirements • (oXirisTM, CytosorbTM, Polymyxin)
(ECMO: extracorporeal membrane oxygenation; MARS: Molecular Adsorbent Recirculation Systems)
68 Section 1  Renal Replacement Therapy

ACTUAL PRESCRIPTION
Prescription for CRRT depends on demands from internal milieu and capacity of kidneys to
deal with the hypercatabolic state with volume and solute overload (Table 5).5

Step 1
Let us consider weight-based effluent dose as a standard for initial prescription and then
keep changing the flow rates as needed. If effluent dose of 30 mL/kg/hr is chosen for a patient
with actual body weight of 60 kg, then total flow rate would be 60 × 30 = 1,800 mL/hr. This is
divided by 2 to get prefilter replacement flow rate (900 mL/hr) and dialysate flow (900 mL/hr).
Postfilter replacement of 200–500 mL/hr may be planned to augment effluent dose for higher
clearances and to prevent clotting in venous chamber. Prefilter replacements preferred, as it
itself prolongs circuit life.6,7

Step 2
After calculating the flow rates, anticoagulation modality (systemic heparin, regional citrate,
or no anticoagulation) is determined based on coagulogram and liver dysfunction. Regional
citrate anticoagulation is safe with liver dysfunction, if citrate levels are kept lower than usual
(<0.21) with careful monitoring for high anion gap metabolic acidosis.8

Step 3
Next step would be to decide upon fluid management. It can be done in two ways.5 We either
keep patient fluid removal (PFR) and ultrafiltration constant and keep changing replacement
flow rates or keep replacement flow rates same and change PFR every hourly. As a unit protocol,
we change ultrafiltration/PFR hourly. Usual prescription for hemodynamically unstable
patient would be to keep in balance. In this, we provide PFR equal to the sum of hourly intake
(enteral + parenteral in mL/hr) and hourly urine output (mL/hr), if any. Conversely, we can
order for net negative balance (PFR exceeding intake per hour) or net positive balance (PFR
less than intake per hour). An important principle governing fluid removal during CRRT is the
concept of plasma refilling rate. During mechanical fluid removal, fluid is primarily removed
from the intravascular compartment. Plasma refilling rates from the interstitial compartment
will determine the rate of change of the intravascular blood volume. If the ultrafiltration (UF)
rate exceeds the plasma refilling rate, decreased blood volume ensues and contributes to
hemodynamic instability. Thus, the CRRT prescription for fluid regulation should take into
account the overall goal for fluid removal (net removal), the rate of removal (how much fluid
is removed in a given time period), patient’s volume status, and the hemodynamic stability
of the patient. Unfortunately, there is no way to easily predict the plasma refilling, and thus, a
cautious “trial and error” approach to fluid removal starting with low-fluid removal rates and
titrating upward as tolerated is a reasonable approach.5

Step 4
Blood flow rate (Qb) is usually kept between 50 mL/min to 150 mL/min and is also subject to
actual body weight and filtration fraction (FF). More the plasma flow less is the FF and chances
Chapter 10  Continuous Renal Replacement Therapy Prescription in ICU 69
of filter clotting. But if citrate regional anticoagulation with prefilled replacement fluid bags is
used (RegiocitTM), then changing blood flow rate would affect citrate dose delivery. Hence, we
would suggest keeping blood flow rates constant with these bags.

ONE SIZE DOES NOT FIT ALL AND ONE IS NOT FIT FOR A SIZE ALWAYS
There could be no default prescription for CRRT. As we know well, CRRT is demand and
capacity-based therapy to help kidney cope with high demands for solute and water
clearance. Hence, as need changes, the prescription changes as well. For high-demand states
(hypercatabolic), higher clearance is needed (higher effluent doses). As kidneys recover, their
capacity is improved and we would need lower effluent doses. If demand increases (worsening
sepsis/shock), we would advise escalating effluent dose/clearance to match the demand
presuming renal function remains unchanged. This only means, we keep changing CRRT
prescription based on patient recovery.

MONITORING WHILE DOING CRRT IN ICU


Monitoring is cornerstone for successful CRRT program. As patients requiring CRRT
are unstable with frequently changing hemodynamic and metabolic parameters, CRRT
prescription needs to alter to fit the changing needs. Monitoring is needed frequently for initial
few hours (q2H) and may be followed less frequently (q6H) once target values are achieved.
Based on results of monitoring (clinical and laboratory), decisions for troubleshooting are
taken. Troubleshooting is made simple, if we follow rule of 10%. That means values for flow
rates (dialysate fluid and replacement fluids), effluent dose or anticoagulation dosing is
altered no more than 10% above or below the previous set value. Only exception would be
very low serum ionized calcium level (<0.8 mmol/L), with regional citrate anticoagulation
where we would suggest bolus calcium gluconate and reducing citrate dose beyond 10% of
previous value (Tables 3 and 4).

Table 3: Monitoring simplified.


Monitoring Frequency Suggested indices
Circuit/filter patency Every 2 hourly till values Heparin: aPTT, activated factor X
normalize followed by 6th Citrate: Postfilter iCa, systemic iCa
hourly
Filter performance Daily once: Preferred in morning Convective: Delivered dose vs prescribed dose
hours Solute: Sieving coefficient, urea clearance,
standard Kt/V
Metabolic/electrolyte As per unit protocol/q6H ABG, lactate, hsCRP, and citrate accumulation
dysfunction index
Other renal parameters Daily once: Preferred in morning CBC, creatinine, urea, total calcium, phosphorus,
hours magnesium, serum albumin, sodium, potassium,
chloride
(ABG: arterial blood gas; aPTT: activated partial thromboplastin time; CBC: complete blood count; hsCRP:
high-sensitivity C-reactive protein)
70 Section 1  Renal Replacement Therapy

Table 4: Frequently used equations.


Equations Expected ranges
Effluent dose (mL/kg/hr) = [Replacement (mL/hr) + 25–35 mL/kg/hr
Dialysate flow + Patient fluid removal ( mL/hr)] / Patient
weight (kg)
Filtration fraction = UF1 rate (mL/min) / Plasma flow rate2 <0.25
to filter (mL/min)
Sieving coefficient = Effluent bag urea / Blood urea >0.7
Urea clearance = Sieving coefficient × Effluent dose 20–30
Citrate accumulation index = [Total calcium (mg/dL) × <0.25
0.25] / Systemic ionized calcium (mmol/L) (<0.21 for people with liver dysfunction)
Ultrafiltration; 2Plasma flow rate Qp = Qb(1 − HCT) Qb = blood flow rate; HCT: hematocrit.
1

Monitoring for fluid status of patient on CRRT is the most challenging of all. We may suggest
relying more on cumulative fluid balance sheets rather than ultrasound/bioimpedance/NT-
proBNP.

WHEN TO STOP/CHANGE OVER?


There are no specific criteria for discontinuation of CRRT because of recovery of kidney
function or transition to other modalities of RRT. An initial manifestation of recovery of kidney
function is increased urine output, although specific criteria are sparse. In the observational
Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) study, a urine output
> 400 mL/day without concomitant diuretic therapy was a predictor of successful CRRT
discontinuation.9 In this observational cohort, patients who were successfully discontinued
from CRRT without requiring reinitiation were more likely to survive to hospital discharge
compared with those requiring reinitiating of CRRT. In another study, urine output > 500
mL/day was proposed as a criterion for discontinuation of RRT in a study of initiation
and discontinuation of therapy in patients with AKI.10 The usefulness of this criterion is
uncertain, however, as the treating clinicians continued RRT despite this recommendation,
approximately two-thirds of the time citing continued volume overload as the most common
reason for continuation of RRT. In the Acute Renal Failure Trial Network (ATN) study, a
6-hour timed urine collection was obtained when the urine output was >750 mL/day.11 RRT
was continued if the measured creatinine clearance was < 12 mL/min, was discontinued if
> 20 mL/min, and was left to clinician judgment if the measured creatinine clearance was
between 12 mL/min and 20 mL/min. Although these strategies can inform clinical decision
making, precise criteria for discontinuation of RRT are lacking.
Factors indicating imminent filter clotting:
■ Sieving coefficient < 0.7
■ Transmembrane pressure (TMP) steadily increasing beyond 200
■ Urea clearance < 20
■ Filtration fraction > 0.25
■ Postfilter ionized calcium > 0.50.
Chapter 10  Continuous Renal Replacement Therapy Prescription in ICU 71

Table 5: Model CRRT/CVVHDF setup with different anticoagulation.


Regional citrate
Machine setup anticoagulation Systemic heparin anticoagulation No anticoagulation
Priming the 0.9 N normal saline 0.9 N normal saline with 0.9 N normal saline
circuit 2000 U UFH
Blood flow 100–150 100–150 100–150
(Qb, mL/min)
Dialysate flow Based on weight and target Based on weight and target Based on weight and
(Qd, mL/hr) effluent dose effluent dose target effluent dose
(Target effluent dose × (Target effluent dose × (Target effluent dose ×
Weight)/2 Weight)/2 Weight)/2
Replacement • *Premixed bags—as per Nil Used only to give saline
PBP (mL/hr) citrate dose flushes (50–150 mL/30
• #ACD bags—200–400 min)
mL/hr: as per postfilter
ionized calcium
Replacement Nil Based on weight and target Based on weight and
prefilter (mL/hr) effluent dose target effluent dose
(Target effluent dose × (Target effluent dose ×
Weight)/2 Weight)/2
Replacement Optional: May be 250–500 Optional: Mainly to increase Optional: mainly to
postfilter (mL/hr) mL/hr (calcium nil effluent dose/avoid venous increase effluent dose/
dialysate)** chamber clotting 250–500 avoid venous chamber
mL/hr (calcium containing clotting 250–500 mL/
dialysate)## hr (calcium containing
dialysate)##
Patients fluid As per volume status As per volume status As per volume status
removal (mL/hr)
Anticoagulation Citrate dose 3 mmol/L— UFH 2,000–5,000 U in venous Nil
titrate as per postfilter line (outflow), 5–10 U/kg/hr Patency of circuit
ionized calcium infusion in prepump segment maintained with saline
flush (PBP)*
Calcium infusion At the end of venous Nil Nil
(outflow) line with three-
way connector
Calcium gluconate 10%
[0.25–0.50 mL/kg/hr]
Titrate as per systemic
ionized calcium
Monitoring Postfilter iCa, systemic iCa, Arterial (inflow) aPTT and Nil
(anticoagulation) and ABG q2H then q6H venous (outflow) aPTT
measured q6H
Monitoring CBC, total calcium, CBC, total calcium, phosphorus, Same
(metabolic) phosphorus, magnesium, magnesium, albumin, creatinine,
albumin, creatinine, BUL, BUL, sodium, potassium,
sodium, potassium, effluent effluent bag urea daily once
bag urea daily once
Additives Prefilled bags: No need Need to add bicarbonate and/ Need to add
to add bicarbonate or or potassium to dialysate bicarbonate and/or
potassium and replacement as per ABG/ potassium as per ABG/
electrolyte levels electrolytes
Contd...
72 Section 1  Renal Replacement Therapy

Contd...
Regional citrate
Machine setup anticoagulation Systemic heparin anticoagulation No anticoagulation
Targets for Postfilter iCa 0.25–0.35 Arterial (inflow) aPTT > 45 sec Nil
optimal mmol/L Venous (outflow) aPTT 1.5–2
anticoagulation Systemic iCa 0.9–1.1 times normal
mmol/L
*RegiocitTM Baxter; #anticoagulant citrate dextrose bags; **BiphosylTM Baxter;## Prismasol B0TM Baxter.
(ABG: arterial blood gas; aPTT: activated partial thromboplastin time; CBC: complete blood count; PBP:
preblood pump; UFH: unfractionated heparin; CRRT: continuous renal replacement therapy; CVVHDF:
continuous venovenous hemodiafiltration)

SUMMARY
■ Initiating CRRT is predominantly a clinical decision supported by laboratory parameters.
■ Indications to start CRRT are mainly nonazotemic, which include hemodynamic instability,
metabolic acidosis, hyperkalemia, and fluid overload.
■ Success of CRRT program hinges on unit protocol for monitoring, troubleshooting, and
continued training for dialysis technicians and nursing staff.
■ World over, ICUs are moving away from systemic heparin to regional citrate anticoagulation
due to better filter life and subsequent shorter downtimes apart from other benefits.

REFERENCES
1. Ronco C, Ricci Z, De Backer D, et al. Renal replacement therapy in acute kidney injury: controversy
and consensus. Crit Care. 2015;19:146.
2. Lameire NH, Flombaum CD, Moreau D, et al. Acute renal failure in cancer patients. Ann Med.
2005;37(1):13-25.
3. Ronco C, Kellum JA, Haase M. Subclinical AKI is still AKI. Crit Care. 2012;16(3):313.
4. Zhang J, Tian J, Sun H, et al. How does continuous renal replacement therapy affect septic acute
kidney injury? Blood Purif. 2018;46(4):326-31.
5. Murugan R, Hoste E, Mehta RL, et al. Acute Disease Quality Initiative (ADQI) Consensus Group.
Precision fluid management in continuous renal replacement therapy. Blood Purif. 2016;42:266-78.
6. de Pont AC, Bouman CS, Bakhtiari K, et al. Predilution versus postdilution during continuous
venovenous hemofiltration: a comparison of circuit thrombogenesis. ASAIO J. 2006;52(4):416-22.
7. van der Voort PH, Gerritsen RT, Kuiper MA, et al. Filter runtime in CVVH: pre- versus post-dilution
and nadroparin versus regional heparin-protamine anticoagulation. Blood Purif. 2005;23(3):175-80.
8. Yu Y, Peng S, Cen Z, et al. Applying regional citrate anticoagulation in continuous renal
replacement therapy for acute kidney injury patients with acute liver dysfunction: a retrospective
observational study. Kidney Blood Press Res. 2018;43(4):1065-74.
9. Uchino S, Bellomo R, Morimatsu H, et al. Discontinuation of continuous renal replacement
therapy: a post hoc analysis of a prospective multicenter observational study. Crit Care Med.
2009;37(9):2576-82.
10. Mendu ML, Ciociolo GR, McLaughlin SR, et al. A decision-making algorithm for initiation and
discontinuation of RRT in severe AKI. Clin J Am Soc Nephrol. 2017;12(2):228-36.
11. VA/NIH Acute Renal Failure Trial Network; Palevsky PM, Zhang JH, et al. Intensity of renal support
in critically ill patients with acute kidney injury. N Engl J Med. 2008;359(1):7-20.
CHAPTER 11
Anticoagulation in Continuous Renal
Replacement Therapy
Pratheema Ramachandran, Ramesh Venkataraman

INTRODUCTION
Continuous renal replacement therapy (CRRT) is often used in hemodynamically unstable
critically ill patients with acute kidney injury (AKI), unable to maintain homeostasis. It is
imperative that the intensivists have a sound knowledge and clear understanding of the
principles, practical and technical aspects of CRRT including choice of modality, timing of
initiation, dose prescription, anticoagulation, monitoring, troubleshooting, and termination
of CRRT.
Optimal provision of CRRT would involve maximizing the duration of filter life, ensuring
quality and dose delivery, while minimizing any related adverse effects. One major concern
in CRRT is the clotting of the circuit and several agents have been evaluated to minimize this.
In this chapter, we overview the existing options, the points in favor and against each of the
agents, and the associated literature.

FACTORS AFFECTING CIRCUIT LIFESPAN


Continuous renal replacement therapy activates coagulation pathway by complex interactions
between the circuit and the circulating blood and leads to clotting of blood within the circuit.
When this happens, solute clearance is reduced, workload and cost of care are increased, and
blood volume loss occurs. Critically ill patients with sepsis or multiorgan failure have high
cytokine levels that can activate the coagulation cascade and the contact of blood with the
extracorporeal circuit further activates the intrinsic coagulation system.1 This leads to clotting
of the circuit, reducing the circuit life. There are multiple reasons for premature clotting of
the circuit2 including high-platelet count, hemoconcentration, turbulent blood flow, stasis
of blood, and contact with air in air detection chambers.2,3 Adsorption of proteins to the
membrane leads to clogging, increase in transmembrane pressures, and eventual clotting.
Interruptions in therapy due to procedures and transfers outside the ICU lead to suboptimal
dose delivery and filter clotting.
Although some nonanticoagulation measures4 such as optimization of vascular access5
(inner diameter, pattern of flow, and position),6 CRRT settings (partial predilution and
74 Section 1  Renal Replacement Therapy

individualized control of filtration fraction), and the training of nurses7 to attend to alarms
immediately improve filter life, anticoagulation is often initiated to prolong CRRT filter life.

ANTICOAGULANTS FOR CRRT


An ideal anticoagulant is one which is easily available, user friendly, safe to use, prolongs
circuit lifespan, and minimizes bleeding risk. While cautious systemic anticoagulation may
lead to inadequate anticoagulation and filter clotting, its overzealous application may lead
to clinically significant bleeds especially in critically ill patients who are already prone to
coagulopathy. Often with safety in mind, clinicians err on the side of no anticoagulation in
high-risk critically ill patients leading to short filter life, provision of inadequate RRT, and
increased treatment costs. Regional anticoagulation techniques provide an opportunity for
optimal anticoagulation of the filter without systemic effects and hence are being increasingly
advocated by experts.

Systemic Anticoagulation
A wide range of drugs (Table 1), of which unfractionated heparin (UFH) is most studied,
are commonly used for systemic anticoagulation in patients on CRRT. Most studies employ
adequate doses and stringent protocols to avoid complications and ensure for effective
outcomes.

Heparin
Unfractionated heparin is the most commonly used systemic anticoagulant;8,9 since it is cheap,
it can be easily titrated and monitored and reversed quickly in the event of any bleeding. It
acts by binding to antithrombin, inactivating factor IIa, Xa, IXa, XIa, and XIIa. With a short
half-life of 60–90 minutes, heparin is metabolized by the liver and eliminated by the kidneys.

Table 1: Comparison of various anticoagulants used in continuous renal replacement therapy.


Loading dose
Drug Half life (IV) Maintenance Monitoring Reversal
UFH 90 min 25 U/kg 5 U/kg/hr ACT, aPTT every 4 hours Protamine
LMWH 10–12 hours 30–40 mg – Anti-Xa every 6 hours Protamine
every 12 hours
Argatroban 35–51 min 250 μg/kg 0.1–2 μg/kg/hr aPTT every 6 hours Factor VIIa
Lepirudin 1–2 hours 0.002 g/kg 0.005 mg/kg/hr ECT every 4 hours Factor VIIa
Bivalirudin 25 min – 1 mg/kg/hr aPTT every 6 hours Factor VIIa
Danaparoid 12 hours – 0.5–1 U/mL anti-Xa Anti-Xa every 6 hours Factor VIIa
Prostacyclin 2 min – 2–8 ng/kg/min No test Stop infusion
Nafamostat 6 min – 0.1 mg/kg/hr aPTT every 6 hours Stop infusion
(ACT: activated clotting time; aPTT: activated partial thromboplastin time; IV: intravenous; LMWH: low-
molecular weight heparin; UFH: unfractionated heparin)
Chapter 11  Anticoagulation in Continuous Renal Replacement Therapy 75
UFH is used both as a systemic and a regional anticoagulant. For systemic anticoagulation,
one study recommended initial bolus of 25 U/kg of UFH and an infusion rate of 5 U/kg/hr.
Monitoring is done using activated partial thromboplastin time (aPTT) or point-of-care testing
with activated clotting time (ACT). The major problems associated with systemic use of UFH
are bleeding, heparin-induced thrombocytopenia (HIT), and heparin resistance.10 Due to its
short half-life and reversibility with protamine (1 mg of protamine will reverse 100 Units of
UFH), its anticoagulant effect can be quickly terminated in cases of significant bleeding.
Systemic UFH combines with platelet factor 4 (PF-4) and triggers the production of
antibodies against these complexes. These antibodies then lead to platelet activation and a
procoagulant state leading to arterial and venous thromboses. HIT is a lethal problem when
not recognized and treated appropriately and hence a high index of suspicion and periodic
monitoring of platelet count (every 48 hours) is necessary for early diagnosis and prompt
treatment. Treatment involves withdrawal of all forms of heparin and initiation of systemic
anticoagulation with an alternate agent, usually a direct thrombin inhibitor.
In patients with sepsis, antithrombin deficiency has been reported leading to heparin
resistance and its ineffectiveness, usually manifested as suboptimal increase in aPTT despite
escalating to high doses of intravenous UFH.8 “Heparin resistance” is usually suspected
when a total daily dose of more than 35,000 IU of intravenous UFH is required to prolong
the aPTT 1.5–2 times from normal mean. Transfusion of fresh frozen plasma (FFP) may be
necessary to replete antithrombin for UFH to be effective in these cases. Ostermann et al.11
performed an audit of a nurse led standardized algorithm-based UFH protocol for CRRT in
10 ICUs. The algorithm seemed to be safe with a filter life of 19.8 hours and with no untoward
effects related to the anticoagulation. Systemic anticoagulation with UFH seems to be a
cheap option and is safe, if based on a user friendly and simple protocol with clear target
points of monitoring.
Low-molecular weight heparins (LMWH): These are fractionated heparins and lack the
ability to inhibit thrombin but provide anticoagulation by their direct antifactor Xa activity.
Unlike UFH, they have a prolonged half-life up to 10 hours and are excreted by kidneys,
theoretically making bleeding complications more likely in comparison to UFH. CRRT
removes LMWH to a clinically relevant extent and, therefore, daily measurement of anti-Xa
activity is essential for monitoring of its anticoagulatory effect. However, the anti-Xa test is
not easily available and expensive making LMWH not an ideal agent for anticoagulation
during CRRT. Furthermore, protamine cannot completely reverse LMWH although the
reversal dose recommended is 1 mg protamine to reverse 1 mg enoxaparin (per 100 anti-Xa
factor). Although the incidence of HIT is lower with LMWH in comparison to UFH due to
their smaller molecular size, these agents should not be used in patients with suspected or
documented HIT.
There were many studies comparing UFH versus LMWH.12,13 Reeves et al.13 compared
dalteparin (22 patients) with UFH (24 patients) undergoing CRRT and found no significant
difference in the time to hemofilter failure (51 hours vs 46 hours, respectively). There was also
no difference in incidence of bleeding episodes or HIT. However, there was a significant cost
difference between the two groups, dalteparin group being the more expensive of the two.
76 Section 1  Renal Replacement Therapy

Direct Thrombin Inhibitors


Direct thrombin inhibitors such as hirudin, lepirudin, bivalirudin, and argatroban have also
been evaluated for anticoagulation in CRRT. These are preferred in patients with suspected or
documented HIT.
Argatroban:14-16 It is a second-generation, direct thrombin inhibitor with a half-life of
35–51 minutes, and administered with a loading dose of 100–250 μg/kg and a maintenance
dose of 0.1–2 μg/kg/min, with dose adjustment in patients with liver disease,17,18 as it is
metabolized by the liver. Monitoring is usually done using aPTT with a target aPTT 1.5–2 times
the baseline. Although its effect wanes off in 2–4 hours after stopping the infusion,19 no specific
antidote exists for reversal of anticoagulation in the event of significant bleeding. It is the agent
of choice for anticoagulation in patients with HIT.
Lepirudin (recombinant hirudin):20,21 It has a half-life of 1–2 hours and dose used is
0.002 g/kg bolus or continuous infusion at 0.005 mg/kg/hr. Ecarin clotting time is more
accurate to monitor hirudin efficacy than aPTT, but often is unavailable for routine clinical care.
Some dialyzer membranes (e.g. polysulfone) bind hirudin, removing it from the circulation
and decreasing its half-life. With an aim of studying the efficacy of lepirudin in CVVH, Hein OV
et al.21 compared intermittent hirudin boluses of 2 mg/kg targeting an ecarin level > 80 seconds
to continuous heparin infusion at 250 U/hr. No bleeding complications were observed with
lepirudin use suggesting safety with its use in this small study.
Bivalirudin: It reversibly inhibits thrombin. It is given as a continuous infusion at 1 mg/hr
targeting aPTT of 1.4 times the baseline. It is the shortest acting among the direct thrombin
inhibitors with a half-life of about 25 minutes. Not many studies are available evaluating
bivalirudin and its usage in CRRT. One trial by Kiser et al.22 compared bivalirudin to UFH
anticoagulation in 10 patients undergoing CRRT and found longer dialyzer filter time with
bivalirudin (29 hours) when compared to UFH (16 hours) with no additional increase in
bleeding complications.
Danaparoid: A low-molecular weight heparinoid with heparin sulfate, chondroitin sulfate
and dermatan sulfate, had been evaluated as an anticoagulant for CRRT in a small study23 in
patients suspected with HIT and was found suitable for this patient population.

Platelet Aggregation Inhibitors


Prostacyclin and nafamostat have been used as regional anticoagulation along with systemic
UFH anticoagulation (hybrid anticoagulation).

Prostacyclin and prostaglandin E1: These are other agents,24,25 which have been evaluated as a
substitute for heparin. These act by inhibiting platelet aggregation, but do not reduce leukocyte
activation commonly seen in sepsis and multiorgan failure. They are generally administered as
a continuous infusion prefilter at a dose of 2–8 ng/kg/min. In spite of their short half-life of 2
minutes, the antiplatelet effect remains for 2 hours. When used as a sole agent,26 they commonly
cause hypotension due to vasodilation, bleeding, and cerebral edema. In one study, Balik et
al.27 compared 17 patients on CRRT on prostacyclin (10 ng/kg/min) and low-dose heparin
Chapter 11  Anticoagulation in Continuous Renal Replacement Therapy 77
(6 U/kg/hr) anticoagulation to 15 patients on CRRT with regional citrate anticoagulation.
There were multiple events of hypotension in the prostacyclin group.
Nafamostat: It is a synthetic serine protease inhibitor prostacyclin analog that has been
evaluated and found to be safer than anticoagulation with regional or low-dose heparin.28
Similar to prostacyclin, it is given as a prefilter infusion at a dose of 0.1 mg/kg/hr. Hyperkalemia,
agranulocytosis, and anaphylaxis are common side effects. Major drawback is that it cannot
be used with negatively charged membranes, like polyacrylonitrile membranes, as it gets
absorbed. A retrospective study29 by Baek et al. examined 243 patients with high-bleeding risk
who were initially started on CRRT with no anticoagulation and had a filter life of less than 12
hours. Out of 243 patients, 62 patients required nafamostat. The filter lifespan was measured
before and after infusion of the drug. The lifespan of the filter was increased from 10 hours to
19 hours with no change in the need for red blood cell (RBC) transfusion.

Regional Anticoagulation
Although systemic anticoagulation helps in maintaining extracorporeal circulatory flow and
increases the efficiency of dialysis by prolonging the circuit and filter life, systemic effects of
anticoagulants like bleeding and thrombosis with HIT are a major concern. Therefore, in an
attempt to prolong circuit life while minimizing the ill effects of systemic anticoagulation, the
concept of regional anticoagulation was introduced. Heparin and citrate have been utilized for
regional anticoagulation.
Regional heparin–protamine anticoagulation (RHPA) protocols were evaluated, with
heparin infused at 1,000–1,500 U/hr in the prefilter circuit. Samples for aPTT are drawn
prefilter and postfilter (maintained at 180–240 sec) and protamine infusion at the rate of
10–12 mg/hr is infused in the return line to reverse heparin. The objective is that the circuit
aPTT should be doubled but systemic aPTT should be maintained normal. The postfilter
protamine dose needed to reverse prefilter heparin may be difficult to calculate, making this
strategy cumbersome and error-prone. In addition, protamine carries its own risks, including
vasodilation, hypotension, pulmonary hypertension, and right heart failure. Vander et al.30
studied different modes of CRRT and RHPA versus systemic nadroparin in 15 patients and
found significant reduction in filter run time with RHPA compared to nadroparin (12.3 vs 39.5
hours, respectively) and increase in bleeding complications. As the protocols are generally
complex and not user friendly, RHPA is not used in clinical practice.

Regional Citrate Anticoagulation


After being introduced in the early 90s, citrate has gained great significance as a regional
anticoagulant. Initially, it was available and used as a 4% solution and was found to increase
circuit lifetime. Since then, numerous protocols have been evaluated for seeking appropriate
regional anticoagulation.

Principle and Mechanism of Action


Citrate is a chelating agent, which reversibly binds with ionized calcium (iCa) interfering
with the coagulation cascade. Citrate forms a complex with iCa, making it unavailable for the
clotting process.
78 Section 1  Renal Replacement Therapy

Technique (Fig. 1)
Citrate comes as a sodium salt3,10 trisodium citrate—usually 40 mg mixed in 1 liter of 5%
dextrose. It is infused separately or as a part of substitution fluid in the prefilter part of the
circuit, hence lowering levels of iCa to nonphysiological levels. The rate of citrate infusion is
usually started at 180 mL/hr and reduced in patients with liver failure or cirrhosis. However,
several protocols exist and regional citrate anticoagulation (RCA) has become increasingly
simpler with the establishment of several protocols.
Titration of citrate dose is done as per blood flow and iCa levels in the postfilter circuit.
Each hospital institution forms their own protocol and follows them, but the objectives and
rationale remain the same.
The objective is to achieve and maintain iCa at a concentration of 0.25–0.4 mmol/L in the
dialysis circuit. At this level of iCa, the coagulation cascade is almost nonfunctional in the
dialysis circuit. This hypocalcemic blood mixed with the citrate solution is circulated to the
hemofilter and as it gets returned to the patient, a calcium chloride is infused intravenously or
through the CRRT circuit to restore normal serum level of iCa. While 50% of the citrate calcium
complexes are removed by the hemofilter, the other 50% enter the systemic circulation. The
citrate entering the systemic circulation gets metabolized in the liver resulting in the generation
of bicarbonate.
Many protocols for RCA have been explored. It should be understood that even though
RCA is known to be the best form of regional anticoagulation with longest filter lives compared
to UFH24 or other anticoagulants used, the efficiency or success of the same is wholly based on
the protocol used. There is substantial heterogeneity in the protocols used for RCA in several
studies and hence outcomes such as filter clotting time, bleeding, need for blood products,
acid–base homeostasis, etc. have been highly variable among the published studies.

Advantages
Regional citrate anticoagulation is now becoming the preferred method of anticoagulation in
CRRT, as it effectively reduces filter clotting time24—increasing circuit life, thereby indirectly

Fig. 1: Regional citrate anticoagulation.


(iCa: ionized calcium)
Chapter 11  Anticoagulation in Continuous Renal Replacement Therapy 79
reducing the requirement of blood transfusions and increasing efficiency of dialysis.
Previously, RCA was considered to be contraindicated in patients with liver failure but with
adequate titration of the dose and careful monitoring, liver failure patients tolerate it better.

Complications
Regional citrate anticoagulation can potentially lead to several clinically important
complications. Citrate accumulation, blood loss, and metabolic alkalosis are all important
complications.
Citrate accumulation: Citrate accumulation, although rare, is the most dreaded complication.
When not metabolized by the liver, citrate accumulates and stays bound to calcium, hence
causing increasing need for calcium replacement. In patients with RCA, the total serum–
calcium should be measured once daily at a minimum. The total calcium will be the sum of the
citrate-bound calcium fraction, iCa, and the protein-bound calcium. Therefore, total calcium/
iCa ratio when high will denote increased amounts of citrate-bound calcium and indicates
citrate accumulation the best. When the ratio exceeds 2.5, a citrate accumulation should
be thought about. Hypoxia increases citrate accumulation as citrate metabolism is oxygen
dependent.
Options for management of citrate accumulation31 include stopping citrate infusion,
decreasing the blood flow rate, thereby decreasing intake through blood flow–citrate
complexes, increasing the rate of dialysate (CVVHD) or the filtration rate (CVVH) (increases
removal), and to adjust citrate concentration within the filter. RCA was believed to be
contraindicated in liver failure patients, the causes being increased citrate accumulation
due to reduced metabolism but recent studies prove the safety profile with liver dysfunction
and failure patients.32.
Blood loss and transfusion requirements: In spite of the regional anticoagulation, some overt
bleeding complications do occur in RCA but are minimal when compared to UFH. The blood
loss and requirement of blood component transfusion can occur in RCA due to filter or circuit
clotting. The circuit volume is around 200 mL and retransfusion is not possible with the clotted
circuit.
Metabolic alkalosis and electrolyte imbalance: 1 mole of citrate gets metabolized to release
3 moles of bicarbonate, hence increased or accumulated citrate causes metabolic alkalosis
and hypernatremia. CRRT with RCA is targeted at providing effective volume control, an
adequate solute clearance and electrolyte and pH stability. Management of metabolic
alkalemia often involves decreasing the citrate concentration and balancing metabolic control
with acid–base homeostasis.
Hypocalcemia: This occurs when adequate calcium is not replaced although in
some protocols, RCA was possible with no calcium infusion as the citrate level was maintained
low.33
Other considerations during RCA include monitoring and management of hypothermia,
hypernatremia, and hypercalcemia.
80 Section 1  Renal Replacement Therapy

No Anticoagulation
In patients with intrinsic coagulopathies and high-bleeding risk, CRRT with no anticoagulation
has been tried. There are also studies which had compared no anticoagulation with low-
dose heparin and regional heparin protamine protocols. The filter life was not very different
between the three groups.34 Adequate flow through vascular access, deaeration of chambers,
reducing number of disconnections, intermittently flushing the circuit with 100–200 mL of
normal saline, and prefilter dilution have been employed in patients with no anticoagulation
and appear to be rather safe in terms of reducing bleeding risk with reasonable filter life.35
Gao et al.36 compared CVVH with RCA with no anticoagulation in 56 patients. No difference
was noted in terms of survival, cost, and length of stay, but RCA group required less blood
transfusion than the no anticoagulation group.

CONCLUSION
■ Unfractionated heparin is widely used systemic anticoagulation but cumbersome
when used as regional anticoagulation with protamine. Complications are HIT, heparin
resistance, and bleeding.
■ Appropriate anticoagulation in CRRT plays an important role in determining the efficacy
of the dialysis. RCA has been by far the best method with a striking difference of longest
filter life and comparatively less complications, but only if based on a user friendly, cost-
effective dose titratable protocol.
■ Regional anticoagulation with citrate is the most preferred method, as it prolongs filter life
and has less bleeding complications.
■ Complications of RCA include metabolic alkalosis, hypocalcemia, and citrate toxicity but
can be prevented with appropriate protocols.
■ Other agents like argatroban, prostacyclin, etc. are evolving but need more trials before
regular usage.
■ More RCTs in future need to be done on no anticoagulation techniques.

REFERENCES
1. Joannidis M, Oudemans-van Straaten HM. Clinical review: patency of the circuit in continuous
renal replacement therapy. Crit Care. 2007;11(4):218.
2. Holt AW, Bierer P, Bersten AD, et al. Continuous renal replacement therapy in critically ill patients:
monitoring circuit function. Anaesth Intensive Care. 1996;24(4):423-9.
3. Baldwin I, Bellomo R, Koch B. Blood flow reductions during continuous renal replacement therapy
and circuit life. Intensive Care Med. 2004;30(11):2074-9.
4. Davies H, Leslie G. Maintaining the CRRT circuit: non-anticoagulant alternatives. Aust Crit Care.
2006;19(4):133-8.
5. Oliver MJ. Acute dialysis catheters. Semin Dial. 2001;14(6):432-5.
6. Schetz M. Anticoagulation in continuous renal replacement therapy. Contrib Nephrol.
2001;(132):283-303.
7. Ramesh Prasad GV, Palevsky PM, Burr R, et al. Factors affecting system clotting in continuous renal
replacement therapy: results of a randomized, controlled trial. Clin Nephrol. 2000;53(1):55-60.
Chapter 11  Anticoagulation in Continuous Renal Replacement Therapy 81
8. Davenport A, Bouman C, Kirpalani A, et al. Delivery of renal replacement therapy in acute kidney
injury: what are the key issues? Clin J Am Soc Nephrol. 2008;3(3):869-75.
9. Bagshaw SM, Laupland KB, Boiteau PJ, et al. Is regional citrate superior to systemic heparin
anticoagulation for continuous renal replacement therapy? A prospective observational study in
an adult regional critical care system. J Crit Care. 2005:20(2):155-61.
10. Amanzadeh J, Reilly RF Jr. Anticoagulation and continuous renal replacement therapy. Semin Dial.
2006;19(4):311-6.
11. Ostermann M, Dickie H, Tovey L, et al. Heparin algorithm for anticoagulation during continuous
renal replacement therapy. Crit Care. 2010;14(3):419.
12. Lim W, Cook DJ, Crowther MA. Safety and efficacy of low molecular weight heparins for
hemodialysis in patients with end-stage renal failure: a meta-analysis of randomized trials. J Am
Soc Nephrol. 2004:15:3192-206.
13. Reeves JH, Cumming AR, Gallagher L, et al. A controlled trial of low-molecular-weight heparin
(dalteparin) versus unfractionated heparin as anticoagulant during continuous venovenous
hemodialysis with filtration. Crit Care Med. 1999;27(10):2224-8.
14. Koster A, Fischer KG, Harder S, et al. The direct thrombin inhibitor argatroban: a review of its use
in patients with and without HIT. Biologics. 2007;1(2):105-12.
15. Di Nisio M, Middeldorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med. 2005;353(10):1028-
40.
16. Link A, Girndt M, Selejan S, et al. Argatroban for anticoagulation in continuous renal replacement
therapy. Crit Care Med. 2009;37(1):105-10.
17. Davenport A, Mehta S. The Acute Dialysis Quality Initiative—part VI access and anticoagulation
in CRRT. Adv Ren Replace Ther. 2002;9(4):273-81.
18. Davenport A. Anticoagulation options for patients with heparin induced thrombocytopenia
requiring renal support in the intensive care unit. Contrib Nephrol. 2007;156:259-66.
19. Link A, Girndt M, Selejan S, et al. Argatroban for anticoagulation in continuous renal replacement
therapy. Crit Care Med. 2009;37(1):105-10.
20. Fischer KG. Hirudin in renal insufficiency. Semin Thromb Hemost. 2002;28(5):467-82.
21. Hein OV, von Heymann C, Diehl T, et al. Intermittent hirudin versus continuous heparin for
anticoagulation in continuous renal replacement therapy. Ren Fail. 2004;26(3):297-303.
22. Kiser TH, MacLaren R, Fish DN, et al. Bivalirudin versus unfractionated heparin for prevention
of hemofilter occlusion during continuous renal replacement therapy. Pharmacotherapy.
2010;30(11):1117-26.
23. de Pont AC, Hofstra JJ, Pik DR, et al. Pharmacokinetics and pharmacodynamics of danaparoid
during continuous venovenous hemofiltration: a pilot study. Crit Care. 2007;11(5):R102.
24. Smith MC, Danviriyasup K, Crow JW, et al. Prostacyclin substitution for heparin in long-term
hemodialysis. Am J Med. 1982;73:669-78.
25. Kozek-Langenecker SA, Spiss CK, Michalek-Sauberer A, et al. Effect of prostacyclin on platelets,
polymorphonuclear cells, and heterotypic cell aggregation during hemofiltration. Crit Care Med.
2003;31(3):864-8.
26. Fiaccadori E, Maggiore U, Rotelli C, et al. Continuous haemofiltration in acute renal failure with
prostacyclin as the sole anti-haemostatic agent. Intensive Care Med. 2002;28(5):586-593.
27. Balik M, Waldauf P, Plášil P, et al. Prostacyclin versus citrate in continuous haemodiafiltration:
an observational study in patients with high risk of bleeding. Blood Purif. 2005;23(4):325-9.
28. Inagaki O, Nishian Y, Iwaki R, et al. Adsorption of nafamostat mesilate by hemodialysis membranes.
Artif Organs. 1992;16:553-8.
29. Baek NN, Jang HR, Huh W, et al. The role of nafamostat mesylate in continuous renal replacement
therapy among patients at high risk of bleeding. Ren Fail. 2012;34(3):279-85.
30. Vander Voort PH, Gerritsen RT, Kuiper MA, et al. Filter run time in CVVH: pre- versus post-dilution
and nadroparin versus regional heparin-protamine anticoagulation. Blood Purif. 2005;23(3):175-80.
82 Section 1  Renal Replacement Therapy

31. Schneider AG, Journois J, Rimmelé T. Complications of regional citrate anticoagulation:


accumulation or overload. Criti Care. 2017;21(1):281.
32. Khadzhynov D, Schelter C, Lieker I, et al. Incidence and outcome of metabolic disarrangements
consistent with citrate accumulation in critically ill patients undergoing continuous venovenous
hemodialysis with regional citrate anticoagulation. J Crit Care. 2014;29(2):265-71.
33. Broman M, Klarin B, Sandin K, et al. Simplified citrate anticoagulation for CRRT without calcium
replacement. ASAIO J. 2015;61(4):437-42.
34. Uchino S, Fealy N, Baldwin I, et al. Continuous venovenous hemofiltration without anticoagulation.
ASAIO J. 2004;50(1):76-80.
35. Tan HK, Baldwin I, Bellomo R. Continuous veno-venous hemofiltration without anticoagulation
in high-risk patients. Intensive Care Med. 2000;26(11):1652-7.
36. Gao J, Wang F, Wang Y, et al. A mode of CVVH with regional citrate anticoagulation compared to
no anticoagulation for acute kidney injury patients at high risk of bleeding. Sci Rep. 2019;9(1):6607.
CHAPTER 12
Goals of Continuous Renal
Replacement Therapy in ICU
Sunitha Binu Varghese, Snehal Gaikwad

INTRODUCTION
Continuous renal replacement therapy or CRRT is therapy intended to substitute for decreased
renal function over an extended period of time (typically for more than 24 hours).1 The basic
goal of RRT when used as replacement modality is to replace the kidneys’ excretory function
to maintain solute, electrolyte, acid base, and fluid homeostasis, promote healing and renal
recovery, while avoid adding insults to the already injured kidney.2 The same RRT techniques
can be used to support recovery of other organs and maintain the internal milieu, e.g. excessive
fluid removal in congestive cardiac failure to help unload the heart, cytokine manipulation in
sepsis or control temperature in malignant hyperpyrexia, etc.2
Due to slow continuous nature of CRRT, it offers advantages of avoiding large shifts in fluids
and osmotically active substances between body compartments with improved metabolic
stability and offers the best hemodynamic stability. Hence, though the basic principles guiding
the use of any modality of RRT remain the same, there are instances where CRRT offers benefit
over conventional intermittent hemodialysis, namely acute kidney injury (AKI) needing
RRT with acute head injury, fulminant hepatic failure, and most importantly hemodynamic
instability with brittle circulation.
Continuous renal replacement therapy also has added advantage: it can be combined with
other forms of extracorporeal life support, e.g. ECMO (extracorporeal membrane oxygenation
and CO2 removal), liver assist techniques, and VAD (ventricular assist devices). Defining the
goals of CRRT in the critically ill patients requires an in-depth understanding of patients’
clinical condition and knowledge of the CRRT technique.
Thus, the goals of CRRT in intensive care unit (ICU) can be summarized as below:
■ Maintenance of solute, fluid, electrolyte, and acid–base homeostasis
■ Prevent further deterioration of renal status
■ Improving hemodynamic stability
■ Removal or modulation of septic mediators
■ Rapid clearance of drugs and toxins
■ Permit organ recovery to occur
■ Nutritional support.
84 Section 1  Renal Replacement Therapy

These goals are achievable depending on the principles, involved in CRRT and the modality
utilized. To achieve the desired goal in ICU, more than one principle may be involved.

PRINCIPLES INVOLVED IN CRRT (TABLE 1) 1,3-5


1. Convection
2. Diffusion
3. Ultrafiltration
4. Adsorption.

MODES OF CRRT
Based on principle of solute and fluid clearance, different modes of CRRT in use today are
listed in Table 2.6
The characteristics of various CRRT modalities are discussed in other chapters in details.

APPLICATION OF CRRT TECHNIQUE TOWARD ACHIEVING


THE SPECIFIC GOALS
Removal of Waste Products (Solute)
The CRRT-specific factors that determine any solute clearance include:
■ Mode of CRRT used—convection (CVVH or CVVHDF) and/or diffusion (CVVHD or
CVVHDF)
■ Qb: Blood flow rate
■ Qd: Dialysis flow rate
■ Qef : Effluent rate, and
■ Filter membrane properties.

Table 1: Examples of uremic solutes and method of clearance during dialysis.5


Solute Molecular weight Example (molecular weight) Method of removal
Small solutes <500 Urea (60), creatinine (113) Diffusion
Middle molecules 500–5,000 Vitamin B12 (1,355) Convection > diffusion
Low-molecular weight proteins 5,000–5,0000 b2 microglobulin (11,800) Convection > diffusion
Large proteins >50,000 Albumin (60,000) Convection

Table 2: Different modes of continuous renal replacement therapy (CRRT) in use today.6
No. Mode Mode Method of solute clearance
1. CVVH Continuous venovenous hemofiltration Convective clearance
2. CVVHD Continuous venovenous hemodialysis Diffusive solute clearance
3. CVVHDF Continuous venovenous hemodiafiltration Convection + Diffusion
4. SCUF Slow continuous ultrafiltration —
Chapter 12  Goals of Continuous Renal Replacement Therapy in ICU 85
Solute clearance of low-molecular weight <500–5,000 Daltons (e.g. urea, creatinine, etc.)
can be efficiently provided by diffusion. Similarly, solute clearance for molecules in the range
of 1,000–20,000 Daltons is higher with CVVH than CVVHD at equivalent effluent flow rates.
Solute adsorption to the filter membrane may add to solute clearance. Till date, with the
available data, no modality is superior to the other; hence, the choice to select CVVH, CVVHD,
or CVVHDF should depend on the resources available and clinician expertise than patient
characteristics and the type of solute clearance desired.

Volume Regulation3,7-9
Fluid management in CRRT can serve two purposes:
■ Adjust the fluid balance of the body, and
■ Adjust plasma composition.

Achieving Fluid Balance


In ICU settings, fluid management patient in critically ill changes on his/her clinical status,
where a balance between fluid delivery and fluid removal needs to be maintained round the
clock to avoid further insults and facilitate organ recovery. The three main objectives to be
kept in mind when trying and achieving fluid balance at all times during the course of illness
are:
■ To remove excess fluid without compromising effective circulating volume and cardiac
output
■ Take into account fluid required to provide adequate nutrition and drugs
■ To maintain urine output.
In critically ill patients with fluid overload, nonresponsive to medical management should
be offered mechanical fluid removal to optimize the fluid balance. RRT is used to achieve fluid
balance through altering the amount of net ultrafiltration rate in such patients.
Net ultrafiltrate = Total ultrafiltrate − Total substitution fluid given
(Total fluid removed) (The plasma water removed)
The target rate at which fluid should be removed should take into consideration:
■ Patient’s hemodynamic status
■ Expected fluid inputs
■ Gastrointestinal and nongastrointestinal losses
■ Expected speed of vascular refilling after fluid removal
■ Degree of tolerance to transient reduction in intravascular volume during the process of
mechanical fluid removal.
Different clinical settings require variations in fluid removal prescription. Varying stage of
illness in the same patient will require alteration in fluid removal. This is the basis of precision
CRRT, one shoe does not fit all.
The goal for mechanical fluid removal in a patient with septic shock at first aims to limit
excess fluid accumulation and prevent further organ injuries then further take care of the
accumulated excess once clinical condition stabilizes.
86 Section 1  Renal Replacement Therapy

Adjusting Plasma Composition


Continuous renal replacement therapy can modify the plasma composition by adjustment
in replacement fluid and dialysate fluid composition. The choice of buffer for CRRT (citrate,
bicarbonate, or lactate) in the dialysate and replacement fluid depends not only the clinical
situation of the patient but also on the available resources.
In patients with impaired hepatic metabolism, as seen in multiple organ dysfunction
syndrome (MODS) where there is lactate acidosis, better control of systemic acidosis and good
improvement in hemodynamic parameters has been shown with use of bicarbonate buffer
in dialysate and replacement fluids. KDIGO guideline suggests using bicarbonate instead of
lactate as a buffer in dialysate and replacement fluid for RRT in patients with:7
■ Acute kidney injury; evidence level (2C)
■ AKI and circulatory shock (1B)
■ AKI and liver failure and/or lactic acidemia (2B).
Other option is to use citrate as buffer, with an advantage that it can provide anticoagulation
as well. CRRT offers advantage over intermittent hemodialysis (IHD)/sustained low-efficiency
dialysis (SLED) in patients with severe hypo- or hypernatremia (sodium <115 or >160 mEq/L)
by precisely varying sodium composition in the replacement fluid and dialysate fluid.

Restoration of Acid–Base Balance10,11


Critically ill patients in ICU often develop mixed acidosis with both respiratory and metabolic
component. In such situations, CRRT is better than IHD because the rate of delivery of
bicarbonate buffer from dialysate to patient is much slower and controlled than IHD.
In ARDS patients, who develop AKI, CRRT when used early in disease course will also
help to titrate the pH in conjunction with the patient’s varying pCO2 in addition to managing
renal insufficiency. Newer extracorporeal techniques implementing removal of CO2 from
extracorporeal circuit offer valuable option to facilitate lung-protective strategies in addition
to solute clearance and correction of systemic acidosis and fluid overload. This removal of CO2
from extracorporeal circuit can be managed by:
■ Use of bicarbonate-free solution as replacement fluid in convective hemofiltration CVVH.
■ Placement of CO2-removing cartridge and a hemofilter is done in series in a venovenous
circuit (ECCO2R). This will help in managing hypercapnia simultaneously with correction
of uremic milieu.
Continuous renal replacement therapy is an efficient means to maintain the body fluid
balance. Lowering of extravascular lung water and interstitial edema will help to improve
ventilatory parameters in ARDS patients.

CRRT Goals in Neurological Disorders3


In neurologic patients, it is important to maintain intracranial pressure (ICP) and cerebral
perfusion pressure (CPP), both within an acceptable range.
When a patient is on RRT, there is rapid removal of urea from blood, so this may aggravate
edema in neurologic patients. Also, sudden change in pH will actually cause paradoxical
Chapter 12  Goals of Continuous Renal Replacement Therapy in ICU 87
intracellular acidosis contributing to edema. Hypotensive episodes during HD may lead to
drop in CPP and rise in ICP due to vasodilatation.
Here, CRRT is better than intermittent therapies due to gradual and gentler correction of
solute, fluid, and acid–base status over extended period of time. Slow change in osmolality
is thus suitable for patients with raised ICP. As larger fluctuations may occur with diffusion-
based therapies, CVVH is preferred over CVVHD. It is reasonable to start with low Qs with high
Na content in replacement fluid.

CRRT Goals in Liver Disorders12


Continuous renal replacement therapy has role in general supportive management of
hepatorenal failure patients requiring dialytic support in acute fulminant/chronic liver failure
and in liver transplant patients.
Goals of CRRT in this setting are:
■ Uremic solutes, ammonia, and free plasma amino acids removal
■ Maintenance of electrolytes, divalent ions, and acid–base balance
■ Maintain precise fluid balance as an aid to nutritional support.
Cerebral edema is one of the defining features of liver failure and hence CRRT is a modality
of choice—causes much slow solute removal, better hemodynamic profile, and prevents
sudden fluctuations in ICP and CPP.
Continuous renal replacement therapy has role in both peri- and postoperative liver
transplant period.
■ Intraoperatively, patients with previously very high portal pressures may develop right-
sided heart failure, which develops due to normalization of systemic vascular resistance
after successful reperfusion of liver. In such situations, CRRT may be used to prevent
development of right side heart failure and also help to correct overall fluid balance and
acidosis.
■ Acute kidney injury in postoperative patients is typically managed by CRRT in the intensive
care unit. In CRRT, slow continuous nature of therapy allows gentle correction of fluid
balance, solutes, and acid–base disturbances with greater cardiovascular stability.

CRRT Goals in Sepsis13,14


Patients with sepsis often develop MODS and AKI. In such patients, guidelines and consensus
suggest CVVH should be considered in preference to IHD/PD, even more so in the presence
of hemodynamic instability. CRRT offers the advantage of preserving systemic and renal
hemodynamics, decreased need for inotropes, improved cardiopulmonary function, and
gradual correction of fluid and metabolic parameters along with possible immunomodulation
and pleotropic benefits.

CRRT Goals in Heart Failure3,10


Primary therapeutic goal of CRRT in patients with refractory volume overload in ADHF (acute
decompensated heart failure) and cardiorenal syndrome type 1 is to safely manage volume
88 Section 1  Renal Replacement Therapy

overload with slow continuous ultrafiltration (SCUF) and/or CVVH in addition to taking care
of azotemia/uremia. Fluid removal in ultrafiltration (SCUF) is iso-osmotic with plasma and
removal of more sodium than with diuretics. Hence, for any given amount of fluid removal,
sodium removal is more in UF than with diuretics. Also, the side effects of diuretics are avoided,
especially the augmented neurohumoral response.

CRRT and Nutrition15,16


The primary goal of CRRT in this context is to permit support measures like nutrition to proceed
without any limitation.
Continuous renal replacement therapy is a highly efficient means of fluid removal. This
reduces the interstitial edema in gut and tissues with improvement of overall fluid balance
of the body. It facilitates early introduction of enteral feeding and avoids use of concentrated
tube-feeding formulas and their limitations, e.g. optimal protein provision. While providing
CRRT, both the amount of fluids required for EN (enteral nutrition) and PN (parenteral
nutrition) are accounted for; hence, this allows much fluid to be used for adequate nutritional
support. Fluids used in resuscitations, giving intravenous medications, as well as EN and PN
feeds are significant sources of sodium in the ICU. The total amount of sodium delivered to the
patient often exceeding the daily recommended intake, which can worsen hypervolemia. This
issue can be addressed with CRRT: both by maintaining optimal fluid balance and with use of
lower sodium content fluids in CRRT to maintain normonatremia.
The amount of calories provided by use of citrate, lactate, and/or glucose-based fluids
used during CRRT should be accounted and taken into consideration when planning the
dietary prescription, especially when using citrate-based anticoagulation. This amount of
nonintentional calories provided will depend upon the type and rate of fluids used.
Continuous renal replacement therapy is slow continuous mode of RRT. This causes loss
of various water-soluble vitamins, electrolytes, essential and nonessential amino acids, trace
element like selenium, etc. more with convective than diffusive therapies. These limitations
should be kept in mind and the nutritionist should in consultation with caregiver, plan the
feeds accordingly.

CRRT Goals in Poisoning and Drug Toxicity3,10,17


Many factors affect drug removal in RRT—drug related and RRT related:
■ Drug characteristics such as solute size, lipid solubility, protein binding, its concentration
gradient between plasma and dialysate, and sieving coefficient of the drug.
■ RRT characteristics such as mode of therapy, filter membrane characteristics, dialyzer
surface area and dialysate/replacement, and blood flow rates.
Those toxins that have large volume of distribution and tight tissue binding often have
slow intercompartmental transfer. In hemodynamically unstable patients with such toxin
poisoning, therapy like continuous hemofiltration can be used to enhance elimination of
toxins.
In conditions like rhabdomyolysis, rapid breakdown of skeletal muscle leads to release
of myoglobin, which has widespread damaging effects on many organs, especially kidneys.
Chapter 12  Goals of Continuous Renal Replacement Therapy in ICU 89
Myoglobin (MW 17,000 Da) is removed efficiently with convective therapies than
intermittent hemodialysis or peritoneal dialysis. However, because of its nonspherical
structure and electrical charge, it has low sieving coefficient, thereby reducing its clearance
with standard CRRT filters. Therefore, the potential use of CRRT (CVVH) with super-high-
flux dialyzers, which have hyperpermeable membrane to improve myoglobin clearance
as intervention to treat and to an extent prevent rhabdomyolysis-induced AKI, is being
studied.
Metformin is commonly used oral hypoglycemic agent with low-molecular weight, poor
protein binding, and large Vd (volume of distribution). The exact etiology of metformin-
induced lactic acidosis is poorly understood but appears multifactorial. Due to slow and
continuous nature of CRRT, it may be a superior choice for treatment in MALAS (metformin-
induced lactic acidosis).

CRRT to Support Renal Recovery18


Loss of renal autoregulation is seen in patients with acute kidney disease. Despite need for
inotropes, these patients often are fluid overloaded (defined as fluid accumulation of over 10%
of baseline weight within a given period of time). This causes increase in renal vein pressure
and renal interstitial edema  leading to reduced renal perfusion, increase intraglomerular
pressure  leading to sustained AKI.
Continuous renal replacement therapy takes care of fluid overload as well as helps by
precisely maintaining fluid balance. The prescription can be tailored to exact needs of the
patient according to phase of acute kidney injury, his volume status, and hemodynamic
status. Improvement in systemic hemodynamics and renal circulation along with removal of
inflammatory mediators released during AKI will help in early recovery of AKI.

CRRT Goals in Inborn Errors of Metabolism10,19


Inborn errors of metabolism known, namely maple syrup urine disease, urea cycle disorders,
organic acidemia, etc. are rare disorders seen in children. The primary goal of RRT in such
children is to reduce the high levels of branched-chain amino acids and ammonia, because
of their potential to induce irreversible central nervous system damage. Hyperammonemia
is more common among them. There are no guidelines defining role of RRT in such settings.
However, studies have suggested the use of RRT to lower the blood ammonia levels to a safe
level may prevent further organ damage. Hence, RRT should be considered in patients with
severe encephalopathy irrespective of blood ammonia levels, and blood ammonia level is
three times greater than the upper limit of normal.
Use of convective therapies, continuous venovenous hemofiltration (CVVH), and
continuous venovenous hemodialysis (CVVHD) rapidly clears these low-molecular weight
toxic metabolites, which help in recovering patients’ neurological status.
To summarize, Table 3 lists the consensus/recommendations for choice of different
modalities of RRT in various clinical settings in AKI.2
90 Section 1  Renal Replacement Therapy

Table 3: Choice of renal replacement therapy (RRT) modality based on clinical setting.
Indication Clinical setting Modality
Uncomplicated ARF Antibiotic nephrotoxicity IHD, PD
Fluid removal Cardiogenic shock, CP bypass, SCUF, CVVH
cardiorenal syndrome type 5
Uremia Complicated ARF in ICU CRRT (CVVHD, CVVH, CVVHDF), SLED, IHD
Increased intracranial pressure Subarachnoid hemorrhage, CRRT (CVVH, CVVHDF)
hepatorenal syndrome
Shock Sepsis, ARDS CRRT (CVVH, CVVHDF)
Nutrition Burns CRRT (CVVHD, CVVHDF, CVVH)
Poisons Theophylline, barbiturates Hemoperfusion, IHD, CVVHD
(ARDS: acute respiratory distress syndrome; ARF: acute renal failure; CRRT: continuous renal replacement
therapy; CVVH: continuous venovenous hemofiltration; CVVHD: continuous venovenous hemodialysis;
CVVHDF: continuous venovenous hemodiafiltration)

CONCLUSION
Though CRRT has many apparent and theoretical advantages in comparison with intermittent
dailysis, there is till date no strong evidence in favor of CRRT in terms of mortality benefit or
renal function recovery. In the intensive care unit the major goals of CRRT can be summarized
as correction of fluid and electrolyte abnormalities, removal of waste products and restoration
of acid/base balance, while maintaining hemodynamic stability.

REFERENCES
1. Bellomo R, Ronco C, Mehta R. Nomenclature for CRRT. Am J Kidney Dis. 1996;28(5):S2-7.
2. Mehta R. Indications for dialysis in the ICU: renal replacement vs. renal support. Blood Purif.
2001;19(2):227-32.
3. Macedo E, Mehta RL. Continuous dialysis therapies: core curriculum. Am J Kidney Dis.
2016;68(4):645-57.
4. Creda J, Ronco C. Modalities of continuous renal replacement therapy: technical and clinical
considerations. Seminars Dial. 2009;22(2):114-22.
5. Avner ED, Harmon WE, Niaudet P, et al. Chapter 73: Hemodialysis. Pediatric Nephrology, 6th
edition. Germany: Springer; 2009. p. 1818.
6. Bellomo R, Kellum JA, La Manna G, et al. Techniques and Modalities of CRRT. 40 Years of
Continuous Renal Replacement Therapy, Volume 194. Contributions to Nephrology. Basel: Karger;
2018. pp. 51-9.
7. KDIGO. (2012). KDIGO Clinical practice guidelines for Acute kidney injury 2012. [online] Available
from: https://kdigo.org/wp-content/uploads/2016/10/KDIGO-2012-AKI-Guideline-English.pdf.
[Last accessed October, 2019].
8. Mehta RL, Clark WC, Schetz M. Techniques for assessing and achieving fluid balance in acute
renal failure. Curr Opin Crit Care. 2002;8(6):535-43.
9. Rosner MH, Ostermann M, Murugan R, et al. Indications and management of mechanical fluid
removal in critical illness. Br J Anaesth. 2014;113(5):764-71.
10. Singh U, Tiwari SC. Nonrenal indications of renal replacement therapy (hemodialysis). JIMSA.
2012;25(2):117-21.
Chapter 12  Goals of Continuous Renal Replacement Therapy in ICU 91
11. Eschelbacher D, Chawla LS, Lew SQ. Correction of respiratory acidosis by continuous renal
replacement therapy. J Appl Res. 2004;4(2):228-33.
12. Davenport A. Continuous renal replacement therapies in patients with liver disease. Semin Dial.
2009;22(2)169-72.
13. Bellomo R, Matson J, Ronco C, et al. Acute Dialysis Quality Initiative 3rd International Consensus
Conference Workgroup. Hemofiltration and Hemoperfusion in Sepsis and Septic Shock. [online]
Available from: https://www.adqi.org/Upload/Reports/ADQI_3/ADQI3g1.pdf. [Last accessed
October, 2019].
14. Ricci Z, Ronco C. Renal replacement II: dialysis dose. Crit Care Clin. 2005;21(2):357-66.
15. Nystrom EM, Nei AM. Metabolic support of the patient on continuous renal replacement therapy.
Nutr Clin Pract. 2018;33(6):754-66.
16. Cano NJM, Aparicio M, Brunori G, et al. ESPEN guidelines on parenteral nutrition: adult renal
failure. Clin Nutr. 2009;28(4):401-14.
17. Keller G, Cour M, Hernu R, et al. Management of metformin-associated lactic acidosis by
continuous renal replacement therapy. PLoS One. 2011;6(8):e23200.
18. Wang XT, Wang C, Zhang HM, et al. Clarifications on continuous renal replacement therapy and
hemodynamics. Chin Med J. 2017;130:1244-8.
19. Gupta S, Fenves AZ, Hootkins R. The role of RRT in hyperammonemic patients. Clin J Am Soc
Nephrol. 2016;11(10):1872-8.
CHAPTER 13
Monitoring during Continuous Renal
Replacement Therapy
Abdul Samad Ansari, Mayur S Shah, Shashank MR

INTRODUCTION
Continuous renal replacement therapies (CRRTs) are today considered as a well-tolerated and
efficient group of treatments for acute renal failure in critically ill patients. In such patients, the
increased morbidity and advanced age require gentle and carefully monitored hemodialysis
therapy. To achieve such results, online monitoring of patient and machine parameters may
become an important issue, although it includes some practical considerations.
Different parameters should be monitored according to the technical and clinical
requirements. Efficiency of CRRT therapy is largely dependent on the continuity of the therapy
and minimizing downtime, which may be attributed to filter clotting, treatment interruptions
due to troubleshooting, etc. Hence, monitoring during CRRT plays a vital role in achieving
a successful therapy.1 Effluent flow rates may need to be increased, if there are frequent or
prolonged interruptions of therapy. Combination of knowledge and expertise leads to safe and
effective delivery of CRRT.2
Continuous renal replacement therapy dose delivery has conventionally been based on the
clearance of urea as a surrogate for low-molecular weight uremic toxins.1 Since small solute
clearance is approximately equal to CRRT effluent flow, the dose of CRRT is expressed as the
effluent volume per unit of time, normalized to body weight.3

PRESCRIPTION4
■ Continuous renal replacement therapy dose identifies the amount of blood cleared of
solute by unit of time.
■ Effluent flow is an acceptable surrogate for prescribing CRRT dose for solute clearance. The
clearance is dependent on the sieving coefficient of the representative solute.
■ Default prescribed CRRT dose should be 20–25 mL/kg/hr for representative small
molecular weight solutes. Urea is the solute most commonly used to quantify dose.
■ Prescribed dose is dynamic. This default prescribed dose can be modified according to
patient demand and in response to iterative evaluation of quality measures. Prescribed
dose should be evaluated at least once every 24 hours and more often.
Chapter 13  Monitoring during Continuous Renal Replacement Therapy 93

Fig. 1: Renal replacement therapy dose delivery [Replicated from www.ADQI.org]. (UF: ultrafiltrate; QM: quality
measure)

DELIVERY4
Dose delivery can be estimated as intensity (mL/kg/hr times the number of treatment hours)
or as time-averaged (average mL/kg/hr over 24 hours or other duration). The Kidney Disease:
Improving Global Outcome (KDIGO) Clinical Practice Guideline (CPG) for acute kidney injury
(AKI) have recommended a default CRRT dose prescription (for urea clearance) of 20–25 mL/
kg/hr effluent flow rate, regardless of the chosen modality or proportion of replacement fluid
given prefilter or postfilter.5
Dose delivery should be routinely reassessed and modified based on iterative evaluation of
quality measures. Dose delivery should be evaluated at least once every 24 hours or more often
as per the patient’s needs (Fig. 1).

FLUID MANAGEMENT DURING CONTINUOUS


RENAL REPLACEMENT THERAPY1
Fluid management during CRRT in critically ill patients is a dynamic process that encompasses
three interrelated goals—maintenance of patency of CRRT circuit, plasma electrolyte and
acid-base homeostasis, and regulation of patient fluid balance.6
■ Circuit integrity:
– Anticoagulation: None/citrate/ultrafiltrate (UF) heparin/low-molecular weight
heparin (LMWH)/other
– Filtration fraction.
■ Plasma composition:
– Type of fluid
– Content
– Site of administration.
94 Section 1  Renal Replacement Therapy

■ Fluid balance:
– Removal
– Regulation.
Filtration fraction (FF): Expressed as,
Ultrafiltrate (UF) rate (mL/min)
FF =
Plasma flow rate (Qp) (mL/min)
where, Qp = Qb (1 − Hct); Qb = Blood flow rate
An increase in UF rate and hematocrit or a decrease in plasma flow rate will increase FF and
thus increase the risk of filter clotting. A high FF (0.25) is typically associated with increased
risk of poor filter performance and clotting due to hemoconcentration-related effects.7

Advantages and Disadvantages of Prefilter and Postfilter Substitution8


Prefilter
Advantages:
■ Ultrafiltrate rate is not limited by Qb.
■ Enhanced elimination of urea from red blood cells (RBC).
■ Filter life is increased as the hematocrit throughout the filter remains low. As filter life
is increased, it may increase solute clearance, even though hourly solute clearance is
decreased.
Disadvantage:
■ Solute concentrations are decreased and thus clearance also is decreased.

Postfilter
Advantages:
■ Clearance of solutes is directly related to UF rate.
■ A higher solute clearance rate is produced.
■ Delivery of specified solutes and concentrations directly to the solution.
Disadvantages:
■ Ultrafiltrate rate is limited by Qb. Higher the UF, higher is the end-filter hematocrit.
■ Because UF rate is limited by FF you may not reach the optimal dose.
■ Filter life may be decreased by high end-filter hematocrit.

Precision Fluid Management1


Fluids administered for circuit patency and anticoagulation need to be included in determining
net fluid balance. Fluids containing alkali (e.g. citrate) will also contribute to the buffer source
and may require adjustment of other fluids to avoid derangements in acid–base homeostasis.7,9
Predilution fluid administration increases filter life and maintains filter patency by reducing
FF.10
Commercially available dialysate and replacement solutions allow flexibility in achieving
various goals of plasma electrolyte compositions to address the majority of clinical scenarios.11
Custom-made solutions should be avoided. Certain situations may arise that require
Chapter 13  Monitoring during Continuous Renal Replacement Therapy 95
production of custom dialysate or replacement solutions.12 In these cases, experienced
pharmacists should be available to compound the solutions and strict quality control measures
should be in place to ensure that errors do not occur.13,14
The choice of dialysate and replacement solution with specific compositions should be
based upon the goals for serum electrolyte and acid–base parameters as well as the choice
of anticoagulation.15 The use of dialysate and replacement solutions must be individualized
and reassessed at frequent intervals (such as every 6–12 hours), depending upon the clinical
condition of the patient, to ensure that they are appropriate.
Replacement solutions should be sterile and dialysate solutions should ideally be sterile or,
at a minimum, be ultrapure.16
Administration of replacement solutions can be either prefilter or postfilter within the
dialysis circuit or outside of it (intravenously). Prefilter replacement of solutions is useful to
minimize filter clotting by reducing the FF but it influences the dose by decreasing solute
concentrations. Postfilter replacement allows direct delivery of solute to the circulation.17
During citrate anticoagulation, frequent measurement of serum ionized calcium (postfilter
and peripherally) should be done to appropriately titrate the dose of citrate and calcium for
replacement. Furthermore, systemic acid–base balance should be closely monitored for the
development of metabolic alkalosis or citrate accumulation.9,18
Clinicians must continuously assess fluid balance and set targets for this variable. These
targets should be used to make an informed decision regarding timing and methods for fluid
withdrawal strategies, be it pharmacological or mechanical.19,20
The goals of care should define the utilization of solutions and fluid balance. Achieving
overall fluid goals require characterization of operating characteristics of CRRT. Flexibility of
changing plasma composition and volume status independently could be tailored to need
of the patient. It is important to recognize that modifying either circuit integrity or plasma
composition or fluid balance will influence the other components.21-23

Principles of Fluid Management in Continuous Renal Replacement Therapy1


■ Total amount of fluid that needs to be removed to achieve clinical goals
■ Ongoing fluid administration needs as well as ongoing net input and output
■ Hemodynamic status (blood pressure, need for ongoing vasopressor support)
■ Rate at which fluid needs to be removed from the patient
■ Need for solute removal, electrolyte correction, or control of uremia
■ Resources available at a particular institution.

Stepwise Fluid Management Prescription in Continuous


Renal Replacement Therapy24,25
■ It is important to determine the effluent volume/hour (UF and/or dialysate flow) required
to provide adequate solute clearance (at a minimum of 30 mL/kg/hr to ensure delivery of
adequate solute clearance).
■ The volume of net UF needed to achieve fluid balance including a reduction of a given
percentage of fluid overload, should be estimated.
96 Section 1  Renal Replacement Therapy

■ The composition of the fluid needed to replace the fluid removed and to meet the goal for
the plasma composition (electrolytes and acid base) should be determined.
■ The timing for achieving the goals and the parameters that need to be monitored should
be prescribed:
– Determine the effluent rate (dialysate and/or ultrafiltrate) needed to meet clearance
goals (recommend starting at 30 mL/kg/hr). Monitor clearance, adjust effluent rate to
meet clearance goals, monitor hemofilter performance [fluid urea nitrogen/blood urea
nitrogen (FUN/BUN)].
– Determine fluid balance needs for the patient and determining the iBalance1 by
incorporating machine and patient fluid balance for regulating net goals. Monitor
hemodynamic response to fluid removal, frequent clinical assessment of fluid removal
goal, flow sheets to monitor machine/patient balance, consider measures of dynamic
fluid assessment.
– Determine composition of replacement and/or dialysate solutions to meet goals of
maintaining electrolyte and acid-base homeostasis. Monitor serum electrolytes and
acid–base status, and adjust fluids accordingly to meet the goals.
– Determine the timing for achievement of goal and monitoring parameters—timing
based upon hemodynamic stability and imperatives based upon clinical goals, set fluid
removal rate, and determine best method to monitor changes.

Monitoring
Monitoring of the circuit integrity, plasma composition, fluid balance, and temperature are
paramount for optimal delivery of CRRT and to avoid complications.26,27
Circuit integrity can be monitored using periodic visual checks of the circuit for any blood
clots or air bubbles. Filter efficacy should be monitored using ratio of effluent fluid to blood
urea nitrogen (FUN/BUN ratio).28 Anticoagulation efficacy should be frequently monitored
using APTT or anti-Xa levels for heparin or LMWH anticoagulation, and postfilter calcium for
citrate-based anticoagulation.29
Access pressures should be monitored to determine adequate circuit blood flow and to
troubleshoot any early circuit issues. Plasma composition should be frequently assessed using
serum chemistry (e.g. 6–12 hours).
Hemodynamic parameters, volume status, temperature, and body weight should also be
monitored (Table 1).17
Complications during CRRT can occur due to inappropriate goal setting, removing too
much or too little volume or due to hemodynamic instability and hypotension.
It is recommended that a patient’s hemodynamic response to fluid removal be monitored
closely and fluid removal rates be adjusted to maintain hemodynamic stability. No study
has demonstrated the superiority of one technique of monitoring over others and clinicians
should, at a minimum, monitor changes in blood pressure at frequent intervals.1,29,30
Given the difficulties in predicting how an individual patient may respond to mechanical
fluid removal, a reasonable approach is to start with a low rate of fluid removal and slowly
increase this to the maximally tolerated rate while monitoring hemodynamic response and
Chapter 13  Monitoring during Continuous Renal Replacement Therapy 97

Table 1: Monitoring variables for CRRT.1


Parameter Measurement Tools
Solute
Very small waste products K+, Na+, phosphate Blood levels of K+, Na+, phosphate, phosphate
clearance, pH, HCO3-, AG, SIDe, SIDa, SIG
Small waste products Urea Clearance
Middle-sized molecules Serum β2 microglobulin β2 microglobulin clearance
Fluid balance Weight Weight changes
Inputs-outputs (fluid Flow sheets
accumulation/overload)
Capillary refill Decreased when hypovolemic
Altered mental status Decreased when hypovolemic
Heart rate Tachycardia may indicate hypovolemic
Blood pressure Decreased when hypovolemic
CVP Absolute and delta gives indication of volume
status
CI PA catheter, PICCO®, FloTrac®
Lactate Increased when hypovolemic
Signs of fluid Indication of volume status
responsiveness (pulse pressure and stroke volume variation,
echocardiography, IVC diameter)
Fluid challenge Indication of volume status
BIA BIVA
BNP BNP profile
(AG: anion gap; BIA: bioelectrical impedance analysis; BIVA: bioimpedance vector analysis; BNP: brain
natriuretic peptide; CI: cardiac index; CRRT: continuous renal replacement therapy; CVP: central venous
pressure; IVC: inferior vena cava; PA: pulmonary artery; SIDa: apparent strong ion difference; SIDe: effective
strong ion difference)

avoiding hypotension causing decrease in end-organ perfusion. The patient’s response to net
fluid removal should be reassessed frequently.21,31
Each unit utilizing CRRT should develop a standardized order set to facilitate fluid
management orders as well as charting parameters and a standardized flow sheet that ideally
can be contained within an electronic medical record. Charting should distinguish CRRT
machine parameters from patient fluid balance parameters and integrate these to provide a
complete fluid regulation analysis.22
Fluid management by CRRT influences patient’s core temperature. Core temperature
should therefore be monitored continuously.1

General Monitoring
■ Temperature: A significant amount of heat is lost as the blood makes its way through the
extracorporeal circuit. Hence, temperature should be monitored from a reliable site every
98 Section 1  Renal Replacement Therapy

2 hours, at least. This is because CRRT patients will drop their temperature by at least 2°C,
despite the fact that dialysate fluid is run through a warmer prior to entering the filter.
Heating lights or warmed blankets are an option, but care must be taken not to cover the
lines as this increases the risk of disconnection. If a patient receiving CRRT is pyrexial,
then it is likely that they have a systemic infection; so WBC and blood cultures should be
checked. The results of these checks will indicate the presence and type of infection, if there
is one.
■ Cardiovascular: Continual cardiac monitoring is necessary because CRRT affects
cardiovascular function, e.g. arrhythmias, as a result of rapid change in serum electrolytes,
such as potassium or magnesium. Regular sampling of blood is required to monitor
electrolyte and acid-base imbalances, so that treatment can be adjusted accordingly and
supplements administered if necessary. Accurate recording of fluid levels is important
to ensure that the patient does not become hyper- or hypovolemic; the patient relies
on external forces to control their internal environment. A common problem when
on continuous venovenous hemodiafiltration (CVVHDF) is hypotension. To maintain
adequate blood pressure, inotropes may be used. The use of a pulmonary artery catheter
and cardiac index gives an indication of the need for fluids or inotropes.17
■ Respiratory: Dialysis can cause changes in a patient’s fluid balance, therefore, it is important
to closely monitor respiratory effort, the use of accessory muscles, signs of tachypnea,
distress, fatigue, and signs of infection (regular sputum samples sent for culture). Such
monitoring is essential to discover or prevent the development of pulmonary edema or
pleural effusion. For patients who require noninvasive or invasive ventilation, need may
arise for an increase in positive end expiratory pressure (PEEP) or pressure support (PS)
requirements. PEEP and PS avoid the overuse of respiratory muscles, which may occur as a
result of acidosis or metabolic derangement caused by dialysis.
■ General observations: In order to maintain the system’s patency, hourly checks of the
vascular catheter site (looking for redness, oozing/bleeding and pain), dialysis lines and
filter pressures should be carried out. These checks give early warning of unwanted side
effects such as accidental disconnection, air in a line or premature clotting of the filter, as
well as signs of infection.
■ Position: The vascular catheter access sites commonly used are via subclavian, internal
jugular, or femoral veins. This may create a problem with positioning the patient as the
line needs to remain patent at all times. Positioning the patient on the vascular catheter
side will often occlude the vascular catheter as the increased pressure causes it to be
advanced slightly. Patients still need to be turned at least every 2nd hour to maintain good
skin integrity. They are often at a higher risk of pressure ulcers due to their compromised
state.
■ Anticoagulation: Most CRRT patients will require some form of anticoagulation, which
should be closely monitored to ensure that optimal anticoagulation is achieved. This will
be assessed according to the type of anticoagulation given.
■ Neurological: Reduced levels of consciousness, increased restlessness, agitation, and
aggression are indications of changes in neurological status. These changes result from
raised creatinine levels, slow excretion of sedatives, and levels of pain. Drugs used for
Chapter 13  Monitoring during Continuous Renal Replacement Therapy 99
treatment of pain need to be very carefully titrated to ensure that the patient is pain-free
but not over-sedated. Need may arise for patient-controlled analgesia (PCA) to control
their pain. A large number of patients those require CRRT will also be septic and hence
require ventilation. This may require the patient to be sedated to maintain comfort and
compliance with ventilation. This often affects the blood pressure, which in turn affects
renal blood flow, possibly worsening renal failure.
■ Nutrition: Another nursing care consideration is the nutrition of the patient, especially if
they are to be dialyzed for a prolonged period of time. Due to the increased metabolic rate
of ill patients, optimal absorption of nutrients consumed does not occur and this can lead
to gut atrophy. The use of enteral feeding is beneficial, as the feed helps to line the gut,
protecting it from gastric acids. If the patient is able to eat normally, then a dietician should
be involved to ensure that a correct balance of nutritious food is supplied. If the patient is
unable to tolerate enteral feeding, total parenteral nutrition (TPN) may be considered.
■ Psychosocial: A dialyzed patient will be concerned, and possibly anxious, about the
machine, of the blood coming out of his/her body and the long-term implications of acute
rheumatic fever (ARF). The presence of uncontrolled pain will add to these fears, as will the
lack of control over what is happening to their body. Regular education of the patient and
family is of utmost importance. To achieve this, simple explanations of ARF and dialysis are
required. The inclusion of a social worker can be beneficial, as are regular visits by family.
■ Indwelling catheter: The development of a urinary tract infection is a side effect of anuria,
as the lack of urine output allows microbes to travel up the catheter.

TREATMENT PARAMETERS
Dosage/prescription:
■ In clinical practice, the “dose” of CRRT is the effluent flow rate (i.e. ultrafiltrate + dialysate).
■ In clinical practice to achieve delivered dose of 20–25 mL/kg/hr, prescription should be in
the range of 25–30 mL/kg/hr.
■ Always check machine-specific dose delivery from the machine data to accurately assess
the difference between prescribed dose and delivered dose.
Blood flow rate:
■ Blood flow rates should be optimized to reduce filter clotting and improve efficacy.
■ However, it should not cross >200 mL/min in CRRT.
Replacement/dialysate rates:
■ Depending on the modality used, dialysate or replacement fluid rates can typically range
between 17 mL/min and 33 mL/min in CRRT.
■ In CVVHDF, the ratio of ultrafiltration to dialysate flow is often set at 1:1, but it can be
altered to put emphasis on either the dialysis or filtration component.
Fluid balance errors:
■ In general, fluid balance errors can be easily avoided, not only by a correct and careful
adherence to protocols of use of machines, but also to compliance to prescriptions and
programed controls during therapy. Non-CRRT input and output must be calculated and
considered.
100 Section 1  Renal Replacement Therapy

■ A fluid balance chart should be updated hourly. For accuracy, it is recommended to check
and possibly record “effectively delivered net UF” and not just mentioning on clinical record
sheet the “prescribed UF”, which can vary significantly due to small errors/interruptions in
therapy.

BIOCHEMICAL AND CLINICAL PARAMETERS


Laboratory values of: Urea, creatinine, sodium, potassium, chloride, bicarbonate, calcium,
phosphate, ABG values, etc. Watch for rapid electrolyte shifts.
Clinical parameters: Mean arterial pressure, sequential organ failure assessment (SOFA) score,
urine output, inotrope requirement, etc.
In case of sepsis monitoring, various sepsis markers would also be helpful, e.g. procalcitonin
level, endotoxin assays, interleukin levels, etc.

Fluid Management
Fluid management during CRRT in critically ill patients is a dynamic process that encompasses
three interrelated goals—maintenance of the patency of the CRRT circuit, maintenance of
plasma electrolyte, and acid–base homeostasis and regulation of patient fluid balance.

Drug Dosing
Removal of drugs by CRRT in critically ill patients is complex, including factors affecting
the patient, drug characteristics, and CRRT procedure. In critically ill patients with AKI,
pharmacokinetic parameters are variable and less predictable than in non-AKI and non-critically
ill patients. Volume of distribution, drug metabolism, and drug elimination are frequently
affected by volume overload, decreased protein binding, and organ blood flow distribution,
among others. Several aspects, e.g. modality selected, filter pore size, membrane type, time of
therapy, use of pre-/postdilution can affect drug clearance and hence need to be considered.

FILTER AND CIRCUIT PARAMETERS


Catheter Troubleshooting
A malfunctioning catheter is suspected when CRRT monitor alarms occur as:
■ Low arterial/access extremely negative or
■ High venous/return extremely positive.

Circuit Pressures
Modern technology CRRT machines allow continuous pressure measurement and display for
both operator and machine interpretation.
Access/machine inlet [negative pressure and return (positive) pressure] depends mostly on
performance of vascular access relative to programed blood flow rate and patient position.
Pressure drop is the gradient of pressure from blood entering and leaving the filter. It
basically defines the capacity of blood to flow through the fibers, or in simple words, it states
the pressure conditions inside the hollow fibers.
Chapter 13  Monitoring during Continuous Renal Replacement Therapy 101

Alarm Systems
Understanding how alarm system works in CRRT is useful for troubleshooting and is an
important aspect of monitoring during therapy. Generally, alarms are classified according
to severity of problem or urgency for attention. They range from advisory alarms with no
immediate error/risk to critical alarms indicating risk and automatic shutdown.

Warning Alarms
Warning alarms occur, if conditions of possible patient hazard exist that require prompt
operator intervention, for example air bubbles in the return line or extreme positive pressure in
the return line. The machine usually enters a “safe state” by stopping all pumps and treatment
is suspended. The patient’s blood does not circulate through the blood flow path.

Advisory Alarms
Advisory alarms occur, if a condition exists of which the operator should be aware, but the
patient is not at immediate risk. The patient’s treatment continues during an advisory alarm.

Caution Alarms
Caution alarms occur if a condition exists for which the proper action is to suspend treatment,
but it is safe to continue blood and syringe pump flow; for example, the pre-blood pump (PBP),
dialysate or replacement solution bag is empty or the effluent bag is full.

The Clogging and Clotting Circuit17


All circuits clot sooner or later and they generally need change of all components of the
extracorporeal circuit. In order to identify and recognize circuit clotting, the following signs
are proposed:
■ Dark streaks through hollow fibers of filters indicate a degree of filter clotting that is
proportional with the total amount of clotted fibers. This sign should be kept under constant
observation.
■ The adsorbed protein layer comprising the secondary membrane also reduces the effective
solute permeability of a CRRT membrane by blocking or plugging a certain percentage
of membrane pores. The adsorptive tendency of a particular filter varies according to
parameters set on the machine. Postdilution tends to promote protein adsorption. On the
other hand, higher blood flow rates work to attenuate this process because the shear effect
created by the blood disrupts the binding of proteins to the membrane surface.
■ Transmembrane pressure’s (TMP) rapid increase is an important sign of hollow fibers
failure, especially during hemo-/ultrafiltration. There is no absolute value to be aware of
but >250 mm Hg is considered indicative of substantial membrane clotting. However, this
also depends on machine setup and filter size. The trend curve of TMP should be observed
because rapid increase in short time frame suggests a threshold of membrane surface area
clotting and imminent total failure.
■ Increase in pressure drop is another important sign of filter clotting. Here too, observing
the trend curve would help in early identification of clotting.
102 Section 1  Renal Replacement Therapy

■ Maintain filtration fraction <15–25% (>25% promotes clotting). Measures like increasing
blood flow to reduce FF in post-dilution, using a filter with larger surface area and using
a combination of pre- and postdilution are some of the measures to reduce filtration
fraction.
■ The deaeration/venous drip chamber may also be a site of circuit clotting during continuous
therapy. Two mechanisms seem to be responsible for clot formation, blood–air interface
and blood stagnation in chamber. Keeping of the chamber at optimal levels would also
help prevent the same. Depending on machine, if using post-dilution replacement, fluid is
added into the deaeration chamber just above the blood. Hence, using a minimum of 200–
500 mL/hr of post-replacement will prevent air–blood interface and help in minimizing
clotting and foaming.
■ Substantial increase in filter pressure drop during treatment is primarily due to filter
thrombosis (Clotting) and while substantial TMP increase during therapy is related to
blood membrane phenomena, especially protein deposition (Clogging).

CONCLUSION
Continuous renal replacement therapy is closely associated with hemodynamics. It is not
only a replacement for organ function but also an important form of hemodynamic therapy.
Improved hemodynamic management of critically ill patients can be achieved by establishing
clear therapeutic hemodynamic targets and maintaining circulatory stability during CRRT.
Continuous renal replacement therapy allows the flexibility of tailoring the fluids
administered or removed to individual needs of the patient and to achieve intended treatment
goals. Precision fluid management and monitoring during CRRT should integrate both
machine and patient fluid balance at frequent intervals to tailor treatment to prevent fluid
overload.
Finally, close observation of renal hemodynamics will provide greater opportunities for the
development and progression of CRRT-associated hemodynamic therapy.

REFERENCES
1. Murugan R, Hoste E, Mehta RL, et al.; Acute Disease Quality Initiative (ADQI) Consensus Group.
Precision fluid management in continuous renal replacement therapy. Blood Purif. 2016;42(3):
266-78.
2. Kellum JA, Mehta RL, Angus DC, et al. The first international consensus conference on continuous
renal replacement therapy. Kidney Int. 2002;62(5):1855-63.
3. Neri M, Villa G, Garzotto F, et al. Nomenclature for renal replacement therapy in acute kidney
injury: basic principles. Crit Care. 2016;20(1):318.
4. Bagshaw SM, Chakravarthi MR, Ricci Z, et al.; ADQI Consensus Group. Precision continuous renal
replacement therapy and solute control. Blood Purif. 2016;42(3):238-47.
5. Ronco C, Bellomo R, Homel P, et al. Effects of different doses in continuous veno-venous
haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet.
2000;356(9223):26-30.
6. Bouchard J, Mehta RL. Volume management in continuous renal replacement therapy. Semin Dial.
2009;22(2):146-50.
7. Joannidis M, Oudemans-van Straaten HM. Clinical review: patency of the circuit incontinuous
renal replacement therapy. Crit Care. 2007;11(4):218.
Chapter 13  Monitoring during Continuous Renal Replacement Therapy 103
8. Macedo E, Mehta RL. Continuous dialysis therapies: core curriculum 2016. Am J Kidney Dis.
2016;68(4):645-57.
9. Tolwani A, Wille KM. Advances in continuous renal replacement therapy: citrate anticoagulation
update. Blood Purif. 2012;34(2):88-93.
10. van der Voort PH, Gerritsen RT, Kuiper MA, et al. Filter run time in CVVH: Pre- versus post-dilution
and nadroparin versus regional heparin-protamine anticoagulation. Blood Purif. 2005;23(3):175-80.
11. de Pont AC, Bouman CS, Bakhtiari K, et al. Predilution versus postdilution during continuous
venovenous hemofiltration: a comparison of circuit thrombogenesis. ASAIO J. 2006;52(4):416-22.
12. Uchino S, Fealy N, Baldwin I, et al. Pre-dilution vs. post-dilution during continuous veno-venous
hemofiltration: impact on filter life and azotemic control. Nephron Clin Pract. 2003;94(4):c94-8.
13. Han SS, Bae E, Kim DK, et al. Dysnatremia, its correction, and mortality in patients undergoing
continuous renal replacement therapy: a prospective observational study. BMC Nephrol. 2016;17:2.
14. Kraus MA. Selection of dialysate and replacement fluids and management of electrolyte and acid-
base disturbances. Semin Dial. 2009;22(2):137-40.
15. Davenport A. Renal replacement therapy in the patient with acute brain injury. Am J Kidney Dis.
2001;37(3):457-66.
16. Zhang L, Chen Z, Diao Y, et al. Associations of fluid overload with mortality and kidney recovery in
patients with acute kidney injury: a systematic review and meta-analysis. J Crit Care. 2015;30(4):860.
e7-13.
17. Hughes RG (Ed). Monitoring during CRRT. Patient Safety and Quality: An Evidence-Based
Handbook for Nurses. AHRQ Publication; 2008.
18. Morabito S, Pistolesi V, Tritapepe L, et al. Regional citrate anticoagulation for RRTs in critically ill
patients with AKI. Clin J Am Soc Nephrol. 2014;9(12):2173-88.
19. Malbrain ML, Marik PE, Witters I, et al. Fluid overload, de-resuscitation, and outcomes in critically
ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol
Intensive Ther. 2014;46(5):361-80.
20. O’Connor ME, Prowle JR. Fluid overload. Crit Care Clin. 2015;31(4):803-21.
21. Xu J, Shen B, Fang Y, et al. Postoperative fluid overload is a useful predictor of the short-term
outcome of renal replacement therapy for acute kidney injury after cardiac surgery. Medicine
(Baltimore). 2015;94(33):e1360.
22. Claure-Del Granado R, Bouchard J. Acid-base and electrolyte abnormalities during renal support
for acute kidney injury: recognition and management. Blood Purif. 2012;34(2):186-93.
23. Huang Z, Letteri JJ, Ronco C, et al. Predilution and postdilution reinfusion techniques. In: Ronco
C, Bellomo R, Kellum J (Eds). Critical Care Nephrology, 2nd edition. Saunders; 2009. pp. 1370-4.
24. Hoste EA, Maitland K, Brudney CS, et al.; ADQI XII Investigators Group. Four phases of intravenous
fluid therapy: a conceptual model. Br J Anaesth. 2014;113(5):740-7.
25. Daugirdas JT. Pathophysiology of dialysis hypotension: an update. Am J Kidney Dis.2001;38(4
suppl 4):S11-7.
26. Davies H, Leslie GD, Morgan D. A retrospective review of fluid balance control in RRT. Aust Crit
Care. 2017;30(6):314-9.
27. Xu J, Ding X, Fang Y, et al. New, goal-directed approach to renal replacement therapy improves
acute kidney injury treatment after cardiac surgery. J Cardiothorac Surg. 2014;9:103.
28. Wang XT, Wang C, Zhang HM, et al. Clarifications on continuous renal replacement therapy and
hemodynamics. Chin Med J (Engl). 2017;130(10):1244-8.
29. Flythe JE, Kimmel SE, Brunelli SM. Rapid fluid removal during dialysis is associated with
cardiovascular morbidity and mortality. Kidney Int. 2011;79(2):250-7.
30. Rabindranath K, Adams J, Macleod AM, et al. Intermittent versus continuous renal replacement
therapy for acute renal failure in adults. Cochrane Database Syst Rev. 2007;(3):CD003773.
31. Schneider AG, Bellomo R, Bagshaw SM, et al. Choice of renal replacement therapy modality and
dialysis dependence after acute kidney injury: a systematic review and meta-analysis. Intensive
Care Med. 2013;39(6):987-97.
CHAPTER 14
Switch Over from or Termination of
Continuous Renal Replacement Therapy
Ajith Kumar AK, Topoti Mukherjee

INTRODUCTION
Although there are better defined criteria for initiation of renal replacement therapy (RRT),
there is no consensus on discontinuation of the same in the critically ill patient. Termination
or discontinuation of continuous renal replacement therapy (CRRT), in simple terms, means
the point at which the clinician anticipates renal recovery or finds acceptable improvement
in the biochemical, acid–base and clinical parameters, and decides to stop CRRT. There are
no standards, no absolute indications, and the decision is often based on empiricism. In this
chapter, we attempt to address the indications for termination of CRRT and the associated
controversies. We will also briefly discuss about the switching over from CRRT to other
modalities before making the conclusion.

WHEN TO TERMINATE CONTINUOUS RENAL REPLACEMENT THERAPY?


Controversies
There is not much data as to when to terminate or stop CRRT, though the decision is easier
for intermittent treatments. A realistic approach to stop CRRT is when the renal functions
improve, either in terms of urine output or blood tests. The available assessment is, however,
not definitive or conclusive in the critically ill patients, nor does it predict the prognosis of
renal or overall recovery.
There are some studies suggesting that perhaps earlier initiation may enable earlier dis­
continuation. A well­defined and prespecified management algorithm (Standardized Clinical
Assessment and Management Plan) has been proposed for initiation and discontinuation of
CRRT to obtain better clinical outcomes.1 In addition, there is no standardized definition for
successful discontinuation from RRT. Successful weaning has varied from 3 days to 30 days in
different studies.2­5

Role of Diuretics
Diuretics may confound the assessment of actual renal recovery. The role of diuretics remains
controversial in acute kidney injury (AKI). A study reported that the use of loop diuretics did not
Chapter 14  Switch Over from or Termination of Continuous Renal Replacement Therapy 105
lead to recovery of AKI, though a prior meta­analysis had shown that the use of loop diuretics
was associated with a shorter duration of RRT.6,7 Despite lack of consensus on their use, it was
hypothesized that they may facilitate discontinuation of CRRT by enabling a favorable fluid
balance. In cases where volume overload is a concern, starting diuretics may be beneficial in
enabling successful discontinuation of CRRT.
Jeon J et al. in their study, concluded that high urine output on day minus one, a shorter
duration of CRRT, and diuretic use favored successful CRRT discontinuation.2

Assessment of Renal Recovery


There are no ideal markers to affirm renal recovery and thereby help the clinician decide
weaning from CRRT. Several markers have been suggested in various studies.
One useful predictor suggested is the 2­hour urine output after a furosemide dose of
2 mg/kg (furosemide stress test) as observed in a retrospective study of 85 patients by FrÖhlich
et al.3 A 2­hour creatinine clearance of 23 mL/min had a sensitivity, specificity, and positive
predictive value of 75.5%, 84.4%, and 88.8%, respectively, for remaining CRRT­free at Day 7.
In this study, 62.4% remained dialysis­free at Day 7 and was a better predictor of remaining
CRRT­free at this time interval compared to serum creatinine or urine output alone.
The optimum urine output cutoff on day minus one as a parameter to discontinue CRRT
has been studied. It has been 191 mL/day for nonoliguric patients, 125 mL/day in oliguric
patients, and 436 mL/day in different studies.2,7
Uchino et al. in their post hoc analysis, concluded that the urine output was the most
important predictor of successful discontinuation of CRRT. In their analysis, a urine output
cutoff of 400 mL per day in those not on diuretics, or 2,300 mL per day in those patients on
diuretics, was a reasonable parameter to guide the clinical decision of discontinuing CRRT.
This was associated with an 80% chance of successful discontinuation.8
In some studies, fractional excretion of urea and furosemide stress test were studied as
predictive markers of discontinuation.9 Creatinine clearance by a 6­hour urine collection has
also been suggested as a predictive marker for renal recovery.10 The calculation was done when
the urine output was consistently >30 mL/hr for 6 hours of collection and when the serum
creatinine showed a downward trend. Renal replacement was continued if the creatinine
clearance was <12 mL/min (0.2 mL/sec) and was discontinued when it was greater than 20 mL/
min (0.3 mL/sec). The decision whether to continue or not in patients falling in intermediate
values of creatinine clearance were at the discretion of the treating clinician. Renal recovery
was considered complete or partial, if the serum creatinine was not more than 0.5 mg/dL
above baseline or more than 0.5 mg/dL above baseline respectively, and when the patient is
not dialysis­dependent.

PREDICTIVE FACTORS FOR SUCCESSFUL TERMINATION OF CRRT


Overall, urine output on day minus one, use of diuretics, and shorter duration of CRRT were
predictive factors for successful termination of CRRT in one study.2
The urine output may be a good marker, but it may be less reliable especially when the
patient has been ultrafiltered high volumes during CRRT to ensure better lung and heart
106 Section 1  Renal Replacement Therapy

compliance. Intensivists tend to monitor the blood gases to determine the need for ongoing
CRRT. It may be prudent to measure the urine output and serum creatinine on a constant dose
of CRRT and calculate the endogenous creatinine clearance by urine and serum creatinine
concentrations. The most predictive factor may be the urine output, but this too may be
negatively influenced by diuretics.
There is a theoretical predictive role of urinary biomarkers of renal injury or function in
patients with AKI. Neutrophil gelatinase­associated lipocalin (NGAL), hepatocyte growth
factor (HGF), and cystatin C (Cys­C) are some of the biomarkers that could potentially predict
renal recovery. Plasma N­terminal pro­brain natriuretic peptide (NT­proBNP) has also been
suggested as a weaning factor.11,12

WHEN TO SWITCH OVER FROM CRRT?


Patients can be considered for switching over from CRRT to a shorter or intermittent renal
replacement modalities, e.g. sustained low­efficiency dialysis (SLED) or intermittent
hemodialysis, once they become hemodynamically stable or are on negligible inotropic
supports compatible at least for SLED. Potential for hemodynamic instability is further high
in intermittent hemodialysis compared to SLED. Switching over to the shorter­duration
modalities might also help to reduce the cost implicated in the continuous procedure. Shorter­
duration treatments will also improve the mobility of the patients for procedures, imaging, or
interventions which cannot be done at the bedside. CRRT may still be the preferred modality
in patients with high intracranial pressure (e.g. acute fulminant hepatic failure or traumatic
brain injury) in view of lesser chances for hypotensive episodes (which could cause cerebral
vasodilation and thereby further increasing the intracranial pressure). Also the slow removal
of urea is less likely to cause rapid intracellular shift of water in CRRT.

WHAT DOES THE EVIDENCE SAY?


There is paucity of data regarding definite indications for discontinuation of CRRT or its
switchover to another modality in a critically ill patient. The decision of when to discontinue
very likely depends on the patient characteristics, physician discretion, timing of initiation and
overall management strategies.
The BEST Kidney (Beginning and Ending Supportive Therapy for the Kidney) was a
multicentric, international epidemiological study of AKI that stated that a urine output of
>400 mL/day without the use of concomitant diuretic therapy, was predictive of successful
discontinuation. In this cohort, patients who were successfully discontinued and did not
require reinitiation of RRT, were more likely to get discharged.13 In continuation with the
BEST Kidney study group, Uchino et al. investigated the ongoing practices of discontinuation
of CRRT in multiple centers. This study was done for 16 months in 23 countries and 54
centers. Clinical (mean arterial pressure, central venous pressure, urine output, diuretic
use, and need for mechanical ventilation or vasopressors) and laboratory data (creatinine,
electrolytes, and blood gases) were collected. Patients were classified as the success group and
the repeat RRT group (those requiring reinitiation of RRT within 7 days of discontinuation).
Chapter 14  Switch Over from or Termination of Continuous Renal Replacement Therapy 107
Patients in the success group were more likely to have a higher urine output and less likely to
have chronic kidney disease (CKD). They also had a lower mortality and a lower duration of
hospital stay. A urine output of 436 mL/day had the highest sensitivity and specificity in the
receiver operating characteristic (ROC) curve of the patients without diuretics. A cutoff of
400 mL of urine per day was therefore chosen as a marker for successful discontinuation of
CRRT. A cutoff of 2,300 mL per day of urine was the cutoff derived for patients on diuretics.8
Wu et al. studied the characteristics of postoperative patients with AKI, but these patients
were on intermittent RRT and their definition of successful discontinuation was being
dialysis­free for 30 days. However, this study also claimed that the urine output is the most
predictive factor of successful discontinuation.4 In another study, 500 mL of urine output
was a cutoff to discontinue CRRT. However, in this study, two­thirds of the time CRRT or
another form of RRT was continued to counter fluid overload.1 Another study [Acute Renal
Failure Trail Network (ATN) study] used a 6­hour urine collection as a parameter to decide
on discontinuation of CRRT. The urine was collected when the previous day’s urine output
was more than 750 mL over 24 hours. The creatinine clearance was calculated on this
sample. RRT was continued when the creatinine clearance was <12 mL/min on this sample
and discontinued when it was >12 mL/min.10 Katayama et al. in their retrospective study,
found that a high urine output, lower creatinine, and a shorter duration of CRRT, were
associated with successful discontinuation.14 Viallet et al., in a small study of 54 patients with
AKI, defined successful weaning as being RRT­free for 15 days after discontinuation and that
a 24­hour creatinine clearance was predictive of successful discontinuation.5 The transition of
patients who have recovered from hemodynamic stability but have persistent AKI to other
modalities of RRT has also not been studied and remains a gray zone. There are again
no guidelines and current practice is purely based on the clinician and other logistic
considerations. Mendu et al. suggested the making of an algorithm for initiation and
discontinuation of RRT in severe AKI.1 It showed that in hospital mortality was lower in
patients with low disease severity whose clinicians adhered to the fixed algorithm. This study
had a cutoff urine output of 500 mL/day for successful discontinuation of CRRT.
The Surviving Sepsis Campaign guidelines15 suggested a pH cutoff of <7.15 to start RRT.
As a corollary to this, a persistent pH of >7.15 may be used as an indicator to stop CRRT.

CONCLUSION
There is no clear consensus on the ideal timing of termination of CRRT in the available
literature. The KDIGO (Kidney Disease Improving Global Outcomes) 2012 guideline16
mentions “Discontinue RRT when it is no longer required either because intrinsic kidney
function has recovered to the point that it is adequate to meet patient needs, or because RRT
is no longer consistent with the goals of care (Not Graded)”. It also suggests not using diuretics
to enhance kidney function recovery, or to reduce the duration or frequency of RRT (2B). The
2016 Japanese guideline17 mentions “Improvements in the clinical data and the urine output
can be used to determine the timing of the blood purification discontinuation (Strength of
recommendation: Not graded, Quality of evidence: C)”.
108 Section 1  Renal Replacement Therapy

The decision of discontinuation of CRRT has to be based on multiple considerations


including the severity of the patient’s clinical condition, the biochemical values, the goals of
therapy, cost of therapy, the modality to switch over to and perceived usefulness of continuation.
A clinician’s sense of renal recovery and anticipated futility in a severely ill patient cannot be
ignored as practical predictors of discontinuation of CRRT.
The decision to discontinue CRRT should be based on one of the following clinical
scenarios:
■ Has the intrinsic kidney function improved?
■ Has the disorder that prompted the renal support resolved?
■ Is continuing CRRT consistent with the goals of care?
A practical approach to guide decision to stop CRRT is when one notices that the renal
functions are clearly improving. This, however, remains a gray zone, and is a subject matter of
the treating physician’s discretion, and also other clinical and biochemical parameters. This
assessment remains conflicting and also individualistic. Filter clotting, cost constraints, and
availability of expertise also remain key factors to be taken into consideration for initiation as
well as discontinuing of CRRT therapy.
We suggest the following approach for discontinuation of or switching over from CRRT,
based on our current practice:
Careful assessment of volume status including a bedside inferior vena cava (IVC)
assessment and lung ultrasound, and hemodynamics are necessary. Also frequent monitoring
of acid–base/electrolyte and metabolic parameters help in decision­making regarding
discontinuation. Achieving an optimal acid–base status along with a negative fluid balance
often remains a major goal in oliguric/anuric patients who have developed AKI. Many patients
with acute respiratory distress syndrome (ARDS) also require a significant negative balance to
maintain oxygenation even with appropriate ventilatory settings.
■ Monitor blood gases frequently and metabolic acidosis consistent with pH of >7.20 in two
consecutive readings taken approximately an hour apart can prompt discontinuation of
CRRT provided all other indications or the goals to initiate the CRRT have been achieved in
an acceptable manner (2D). We consider reinitiating CRRT (or start on other intermittent
modalities, if possible) at any stage after discontinuation, if there is an urgent or elective
RRT indication occurs.
■ If the previous day’s (24 hours) urine output is more than 400 mL, we do consider stopping
CRRT, if other metabolic/acid–base/electrolyte parameters are within acceptable
limits. If the urine output is less than 400 mL and if the other metabolic parameters are
still acceptable (and other goals achieved) with the patient clinically improving, we still
consider discontinuing CRRT (2C).
■ We stop CRRT if the filter clots (unplanned event). Unplanned stopping may also be
warranted, if the patient requires any radiologic imaging or other interventions not feasible
at the bedside. Discontinuation may be required, if the hemodialysis (HD) catheter is not
adequately patent. In such circumstances, we continue to monitor acid–base/electrolyte/
metabolic and fluid status parameters and reinitiate CRRT electively, if indicated in the
coming hours.
Chapter 14  Switch Over from or Termination of Continuous Renal Replacement Therapy 109
■ We frequently consider switching over to other modalities (e.g. SLED or intermittent
hemodialysis) while the patient is on CRRT or after each discontinuation of a CRRT. The
patients need to become hemodynamically stable or should be on negligible inotropes to
be compatible for such modalities (1B). One major reason to consider switching over to
intermittent modalities is cost implication (2C). We still prefer to continue CRRT in patients
with increased intracranial pressure including acute fulminant hepatic failure or traumatic
brain injury (2C). We prefer CRRT also in oliguric/anuric ARDS patients, since CRRT can
achieve a better net fluid negativity without causing significant hemodynamic instability
(2D).Finally, we consider discontinuing CRRT after discussion with the patient’s relatives,
if the expected outcome is extremely poor, thereby questioning the very ethicality of such
a management. However, as per the current Indian legal status, only reinitiation (after a
discontinuation) could be withheld once a consensus decision between the treating team
and family members is made.
Some centers continue CRRT in all anuric/oliguric patients till the filter clots, irrespective
of normalization of the metabolic parameters/fluid status in order to ensure continuous
slow “physiologic” renal support. Few experts consider giving a furosemide challenge (1–1.5
mg/kg) and watch for adequate diuretic response before reinitiating CRRT, once it has been
discontinued in a planned or unplanned setting. Few centers routinely stop CRRT after about
24 hours and watch for a consistent diuretic response, once the acid–base status and target
ultrafiltration have been achieved. Close monitoring of acid–base/electrolyte status and
oxygenation is done during this trial of long break period (before reinitiation), which is expected
to reduce the CRRT costs. Also, the hemodynamics is expected to improve in the ensuing hours
or days, which might give an option of switching over to a less expensive intermittent therapy.

REFERENCES
1. Mendu ML, Ciociolo GR Jr, McLaughlin SR, et al. A decision­making algorithm for initiation and
discontinuation of RRT in severe AKI. Clin J Am Soc Nephrol. 2017;12(2):228­36.
2. Jeon J, Kim DH, Baeg SI, et al. Association between diuretics and successful discontinuation of
continuous renal replacement therapy in critically ill patients with acute kidney injury. Critical
Care. 2018;22(1):255.
3. Fröhlich S, Donnelly A, Solymos O, et al. Use of 2­hour creatinine clearance to guide cessation of
continuous renal replacement therapy. J Crit Care. 2012;27(6):744.e1­5.
4. Wu VC, Ko WJ, Chang HW, et al.; National Taiwan University Surgical ICU Acute Renal Failure
Study Group (NSARF). Risk factors of early redialysis after weaning from postoperative acute renal
replacement therapy. Intensive Care Med. 2008;34(1):101­8.
5. Viallet N, Brunot V, Kuster N, et al. Daily urinary creatinine predicts the weaning of renal
replacement therapy in ICU acute kidney injury patients. Ann Intensive Care. 2016;6(1):71.
6. van der Voort PH, Boerma EC, Koopmans M, et al. Furosemide does not improve renal recovery
after hemofiltration for acute renal failure in critically ill patients: a double blind randomized
controlled trial. Crit Care Med. 2009;37(2):533­8.
7. Bagshaw SM, Delaney A, Haase M, et al. Loop diuretics in the management of acute renal failure:
a systematic review and meta­analysis. Crit Care Resusc. 2007;9(1):60­8.
8. Uchino S, Bellomo R, Morimatsu H, et al. Discontinuation of continuous renal replacement
therapy: a post hoc analysis of a prospective multicenter observational study. Crit Care Med.
2009;37(9):2576­82.
110 Section 1  Renal Replacement Therapy

9. Chawla LS, Davison DL, Brasha­Mitchell E, et al. Development and standardization of a furosemide
stress test to predict the severity of acute kidney injury. Crit Care.2013;17(5):R207.
10. Palevsky PM, Zhang JH, O’Connor TZ, et al.; VA/NIH Acute Renal Failure Trial Network. Intensity
of renal support in critically ill patients with acute kidney injury. N Engl J Med. 2008;359(1):7­20.
11. Srisawat N, Murugan R, Lee M, et al.; Genetic and Inflammatory Markers of Sepsis (GenIMS)
Study Investigators. Plasma neutrophil gelatinase­associated lipocalin predicts recovery from acute
kidney injury following community­acquiredpneumonia. Kidney Int. 2011;80(5):545­52.
12. Srisawat N, Wen X, Lee M, et al. Urinary biomarkers and renal recovery in critically ill patients
with renal support. Clin J Am Soc Nephrol. 2011;6(8):1815­23.
13. Uchino S, Kellum JA, Bellomo R, et al.; Beginning and Ending Supportive Therapy for the Kidney
(BEST Kidney) Investigators. Acute renal failure in critically ill patients: a multinational, multicenter
study. JAMA. 2005;294(7):813­8.
14. Katayama S, Uchino S, Uji M, et al.; Japanese Society of Education for Physicians and Trainees
in Intensive Care (JSEPTIC) Clinical Trial Group. Factors predicting successful discontinuation of
continuous renal replacement therapy. Anaesth Intensive Care. 2016;44(4):453­7.
15. Dellinger RP, Carlet JM, Masur H, et al.; Surviving Sepsis Campaign Management Guidelines
Committee. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic
shock. Crit Care Med. 2004;32(3):858­73.
16. KDIGO Clinical Practice Guidelines for Acute Kidney Injury. Criteria for stopping renal replacement
therapy in AKI. Kidney International Supplements. 2012;2(1):93­4.
17. Doi K, Nishida O, Shigematsu T, et al.; The Japanese Clinical Practice Guideline for Acute Kidney
Injury 2016 Committee. The Japanese clinical practice guideline for acute kidney injury 2016. Clin
Exp Nephrol. 2018;22(5):985­1045.
CHAPTER 15
Continuous Renal Replacement Therapy in
Specific Situations/Diseases
Prakash Jiandani, Gunjan Chanchalani

Continuous renal replacement therapy (CRRT) provides continuous clearance without


metabolic fluctuations, enables continuous and dynamic fluid management, and minimizes
fluctuations in fluid status, and also can be relatively easily combined with other continuous
therapies. Hence, CRRT is the preferred modality of therapy in many conditions.

CONTINUOUS RENAL REPLACEMENT THERAPY IN


SEPSIS AND MULTIORGAN FAILURE
Continuous renal replacement therapy has two major roles in sepsis and multiorgan failure—
first for septic acute kidney injury (AKI), and second for immunomodulation.1
Continuous renal replacement therapy is the most favored renal replacement therapy for
septic AKI, as it helps to prevent hemodynamic fluctuations in an unstable patient. Details
of appropriate timing, effluent dose, and other details have been explained in previous
chapters.
Continuous renal replacement therapy also plays a role in elimination of inflammatory
mediators by convention, with a cutoff value of 30–40 kDa of a standard CRRT high-flux
membrane. Except for IL-10 and TNF-α, most of the other cytokines can be removed slowly
by CRRT.2 However, research has failed to show any major change in the plasma cytokine
concentration with the use of CRRT. Use of high-volume hemofiltration or use of membrane
with high cutoff are shown to increase the clearance of cytokines, but clinical benefit is still not
clear.3
Initial pilot studies using high-volume hemofiltration (HVHF) (effluent dose > 35 mL/kg/hr;
and at times up to 125 mL/kg/hr) showed a reduction in cytokine levels and improved
hemodynamics.4 However, a Cochrane review conducted in 2013 found only three studies of
sufficient quality, and reported insufficient evidence to recommend HVHF in septic critically
ill patients, except for the purpose of randomized trials.5 Another prospective, randomized,
open, multicenter trial, the IVOIRE [high-volume versus standard-volume hemofiltration for
septic shock patients with acute kidney injury (AKI)] trial was terminated prematurely and did
not find difference in the mortality or organ function.6 One more randomized trial,7 reported
112 Section 1  Renal Replacement Therapy

reduction in the levels of certain cytokines in the first 24 hours in the HVHF group; however, no
difference in the outcome was found.
Probably the failure HVHF can be explained by ineffective cytokine clearance at the
cellular level. Also, significant removal of antibiotics and thus subtherapeutic plasma levels
may be another reason for the failure of therapy. Electrolyte disturbance and depletion of
micronutrients, may be other contributors.8
In vitro studies showed use of high cutoff membranes (cutoff 60–150 KDa) for HVVF, as an
efficient way to remove cytokines. However, despite greater removal of cytokines, clinical trials
have failed to show a significant decrease in the circulating levels of cytokines in the plasma,
with the use of super high-flux filter at standard continuous venovenous hemofiltration (CVVH)
dose.9 oXiris hemofilter is a high-permeability polyacrylonitrile (AN69)-based membrane, on
which a positively charged polyethylenimine surface treatment has been added. It has shown
to have high adsorptive capacity for both cytokines and endotoxins.10 A recent retrospective
cohort study showed a significant improvement in the hemodynamics in the first 48 hours of
use along with better lactate clearance with the use of oXiris membrane. Also, better survival
predicted by the SAPS II severity score was reported for the most severe patients. The benefit
was seen more in patients with Gram-negative bacterial (GNB) infections and intra-abdominal
sepsis.11
Till date, no consensus has been reached about which technique of extracorporeal blood
purification offers most benefit. But the use of standard CRRT for immunomodulation, in the
absence of AKI, cannot be recommended as per current research.

CONTINUOUS RENAL REPLACEMENT THERAPY IN


DECOMPENSATED HEART FAILURE
Slow continuous ultrafiltration (SCUF) and CVVH/continuous venovenous hemodialysis
(CVVHD) are the modalities of CRRT, which have shown benefit in cardiorenal syndrome, by
unloading the failing heart and also restoring cardiac and renal function.
Fluid removal by SCUF at a slow rate helps provide hemodynamic stability, with
symptomatic relief in pulmonary edema. It has also shown to reduce plasma renin,
norepinephrine and aldosterone levels, thus preserving cardiac index and renal perfusion
pressures.12 Early use of SCUF in patients with the New York Heart Association (NYHA) class
IV and diuretic resistance, showed improved symptoms at 30 and 90 days.13 The Relief for
Acutely fluid-overloaded patients with decompensated congestive heart failure (RAPID-
CHF) trial compared the use of diuretics only with use of SCUF with diuretics, and found a
significant symptom improvement in the SCUF group.14 The UNLOAD trial in decompensated
heart failure (DHF) patients refractory to diuretic therapy, showed decreased rate of
rehospitalization in the SCUF group. However, it found no difference in the dyspnea scores,
and serum creatinine and urea nitrogen levels.15
Use of CVVH in DHF offers additional benefit in correcting metabolic parameters along
with fluid removal. Correction of hypocalcemia is one such potential benefit, though data is
still lacking.16 Solute clearance achieved with CVVH helps removal of “myocardial depressant
cytokines” via convention.17 IL-8 and anti-monocyte chemoattractant protein-1, are two
Chapter 15  Continuous Renal Replacement Therapy in Specific Situations/Diseases 113
specific cytokines found to be effectively removed by hemofiltration in patients with DHF.
However, no significant clinical benefit has been shown with the reduction in the serum
cytokine concentration. A trial in 2013 compared the use of CRRT with the use of diuretics
in NYHA III-IV heart failure patients. CRRT was used only in patients with renal dysfunction
or refractory to diuretics. Both CRRT and diuretics showed significant clinical improvement,
but only CRRT showed a significant improvement in radiographic signs, echocardiographic
pressures, and biohumoral variables, namely N-terminal probrain natriuretic peptide (NT-
proBNP) and lactic acid concentration.18
A recent trial compared the CRRT modalities—SCUF vs CVVH in patients with cardio-
renal syndrome, and found better survival as well as longer mean survival time, probably
a result of better preserved hourly urine output and cytokine removal, respectively with
CVVH.19
There still lacks consensus regarding patient selection for SCUF/CVVH. Guidelines for
acute DHF do not give any specific recommendations, though the 2008 ESC guidelines20
recommend use of dialysis (not specific for CRRT) only in patients with coexisting renal
dysfunction with creatinine more than 5. Also, there are no established clinical or biochemical
indicators about when to stop the extracorporeal fluid removal and support.
Slow continuous ultrafiltration is preferred in patients with DHF and preserved renal
function, whereas CVVH is the method of choice in patients with cardiorenal syndrome.

CONTINUOUS RENAL REPLACEMENT THERAPY IN


ACUTE NEUROLOGICAL INJURY
Continuous renal replacement therapy is preferred over intermittent dialysis techniques in
patients with acute neurological injury, as it has shown to decrease surges in intracranial
pressure and better stability of cerebral perfusion pressure. Also, filtration is the preferred
modality over dialysis, due to slower change in serum urea levels and better cardiovascular
stability. Predilution fluid replacement with a sodium concentration more than 140 mmol/L
should be used initially.21
A retrospective study published in patients with traumatic brain injury and impending
acute renal failure (ARF) has shown that early use of CRRT before reduction in urine output to
less than 500 mL per day, significantly prolonged survival time.22
In neurotrauma patients, requiring renal replacement therapy (RRT), imaging studies do
not show increased water content in the brain, as compared to intermittent dialysis.23 Use of
regional anticoagulation nearly eliminates the risk of bleeding. And hence CRRT is now the
preferred modality of choice in patients with neurotrauma/brain injury with raised intracranial
pressure.24
Also, CRRT helps clearance of drugs/toxins causing coma and metabolic encephalopathies
and has the advantage in preventing rebound increase in plasma concentrations as compared
to intermittent techniques.
Use of high-volume hemofiltration with or without mild hypothermia up to 8 hours, had
shown to improve survival, even without AKI, in resuscitated post-cardiac arrest patients.25
Further studies are still awaited.
114 Section 1  Renal Replacement Therapy

CONTINUOUS RENAL REPLACEMENT THERAPY IN LIVER DISEASE


Acute kidney injury in liver disease can be multifactorial—ranging from hepatorenal syndrome,
preload responsive AKI, tubulointerstitial or glomerular involvement. Use of RRT in liver disease
is mainly a supportive measure for regulation of water, acid-base, and electrolyte balance.
For removal of potential toxins, both free amino acids and ammonia, use of CRRT has no
significant impact unless improvement in hepatic function.26
Use of CRRT in hepatorenal syndrome has the advantage of better hemodynamic stability
compared to intermittent techniques, as well as helps maintain sodium levels in a controlled
manner.27
In fulminant liver failure, patients are at risk of hypotension due to circulating nitric oxide
levels and also rapid clearance of urea can exacerbate cerebral edema. Thus, CRRT becomes the
modality of choice as it gives the best cardiovascular and cerebral stability. The hypothermia,
which occurs during CRRT, has the advantage to further reduce intracranial pressure.28 Also,
high-volume CRRT has shown to remove unidentified compounds that accumulate in liver
failure. Use of high-volume CRRT along with plasmapheresis has shown to improve 28-
day survival in patients with fulminant hepatic failure.29 When serum ammonia levels were
compared in patients with acute liver failure, ammonia reduction was significantly more with
CRRT, as compared to intermittent hemodialysis (IHD) or no dialysis. After adjusting for age,
etiology, and disease severity, CRRT showed a reduction in 21-day transplant-free all-cause
mortality, whereas IHD had shown an increase in the same.30
Continuous renal replacement therapy is preferentially being used in liver transplant
patients, not only as a bridge to transplantation but also in the intraoperative and postoperative
period. It helps in maintaining acid-base and fluid balance, with better hemodynamic stability.
Use of RRT in patients awaiting orthotopic liver transplantation has shown a poor survival to
transplantation of only 33%, irrespective of use of IHD or CRRT.31 Townsend et al.32 showed that
use of intraoperative CRRT helped maintain negative or equal fluid balance, despite multiple
blood transfusions. He reported a circuit clotting in 40% cases, despite elevated international
normalized ratio (INR). However, anticoagulation was avoided due to fear of bleeding.
Due to poor metabolism of lactate in patients with liver disease, dialysate and replacement
fluids without lactate, have been found to be superior.33
Anticoagulation during CRRT has always been a concern in liver disease patients. They have
increased circulating tissue factor, secondary to the disseminated intravascular coagulation
(DIC). Despite deranged coagulation, they have an increased tendency for circuit clotting. Due
to potential risk of bleeding, anticoagulation-free CRRT is usually performed. Other options
are regional anticoagulation with citrate. Except in severe cases, citrate can be used in patients
with liver failure.34 Heparin is safely used in posttransplant patients.

CORRECTION OF SEVERE ELECTROLYTE AND ACID–BASE ABNORMALITIES


Continuous renal replacement therapy allows predictable and controlled correction of acid–
base and electrolyte abnormalities.
Patients with extreme dysnatremias (with plasma sodium < 120 mEq/L or > 165 mEq/L) are
best treated with CRRT.35
Chapter 15  Continuous Renal Replacement Therapy in Specific Situations/Diseases 115
In cases with severe fatal hyperkalemia, with arrhythmias or with rapid ongoing
potassium generation (like in tumor lysis syndrome and rhabdomyolysis) initial conventional
hemodialysis should be initially given and later switched to CRRT. Patients with high potassium
regeneration exceeds the removal capacity of CRRT, despite high dialysate and replacement
fluid rates. Similarly, fatal symptomatic hypermagnesemia should be initially treated with
intermittent dialysis.35
Continuous renal replacement therapy offers advantage for correction of metabolic
acidosis, as it effectively exchanges anions (e.g. chloride, lactate, and phosphate) with
bicarbonate, without causing concurrent sodium load. Historically, lactate-based solutions
were used as a buffer but with the availability of twin-chamber fluid bags, stability and shelf-
life of bicarbonate-based solutions has improved. The use of bicarbonate-based solutions
has the advantage of not masking lactate overproduction and hence serum lactate levels
can be reliably used for monitoring tissue perfusion.35 Levraut et al.36 measured total plasma
and hemofilter lactate clearance in 10 patients with stable lactate acidemia treated with
continuous venovenous hemodiafiltration (CVVHDF). He found a high endogenous total
plasma clearance of 1,379 mL/min and a median hemofilter lactate clearance of less than
40 mL/min. The highest available bicarbonate in CRRT fluid is 35 mEq/L, and hence the
dialysate flow rates should be adjusted as per the patient’s needs.

REMOVAL OF EXOGENOUS AND ENDOGENOUS TOXINS


Removal of toxins and substances through CRRT depends on multiple factors like ultrafiltration
coefficient of the filter, molecular size, protein binding and its volume of distribution, and the
treatment characteristics. CRRT filters allow removal of molecules with 30–40 kDa molecular
weight, whereas with high cutoff filters removal of molecules up to 65 kDa molecular weight
can be achieved. The main determinant of clearance is the CRRT blood flow rate, and high
effluent flows allow high removal of the substance. For removal of small-size molecules (500–
1,000 Daltons), higher dialysate flows should be achieved and for the removal of middle-sized
molecules, lower dialysate flows permitting more convective clearance is preferred.37
Continuous renal replacement therapy is the preferred modality for removal of exogenous
toxins like lithium, alcohols, salicylates, and valproate, as it prevents rebound increase in the
plasma levels on cessation of therapy as with intermittent methods.38 In sodium valproate
poisoning, CRRT helps in simultaneous removal of valproate and ammonia that is generated.
It is safer than IHD, as such patients are at risk of cerebral edema.39
Continuous renal replacement therapy helps effective removal of ammonia (secondary to
both liver and non-liver pathology), at clearance limit equivalent to that of urea. The likely
benefits of CRRT over IHD are unclear in rhabdomyolysis.

CONTINUOUS RENAL REPLACEMENT THERAPY IN NEONATES


The most common indication of CRRT in neonates is mainly in neonatal hyperammonemia,
secondary to inborn errors of metabolism. A recent study found no significant difference in the
survival whether hemofiltration or hemodiafiltration was used. Higher rates of dialysate and
replacement fluids help reduce the ammonia levels faster.40
116 Section 1  Renal Replacement Therapy

CONTINUOUS RENAL REPLACEMENT THERAPY IN PREGNANCY


Continuous renal replacement therapy along with plasmapheresis has been studied in five
pregnant patients diagnosed with acute fatty liver of pregnancy, and coexisting renal failure.
Early use of plasmapheresis with CRRT helped maintain hemodynamic stability, water–
electrolyte balance, and rapid correction of metabolic parameters. The authors concluded that
early initiation of plasmapheresis with CRRT, in patients with potentially fatal acute fatty liver
of pregnancy with coexisting renal failure, is safe and effective.41

TAKE HOME MESSAGES


■ Continuous renal replacement therapy offers clinical benefit over intermittent dialysis in
septic shock as it maintains better hemodynamic stability. Its use for blood purification in
sepsis without AKI is not recommended.
■ In DHF, SCUF can be used to control volume overload, but in patients with cardiorenal
syndrome, CRRT is preferred.
■ Continuous renal replacement therapy helps gradual correction of sodium levels in severe
dysnatremias. But in life-threatening dyselectrolytemias, intermittent techniques are
preferred over CRRT.
■ Continuous renal replacement therapy is the modality of choice in patients with acute
brain injury, both traumatic and nontraumatic.
■ Similarly, in liver disease, CRRT helps in better control of hemodynamic, acid–base
and electrolyte balance, and is preferentially used in liver transplant patients, in the
peritransplant period.
■ Preventing rebound increase in the plasma toxin levels, makes CRRT a preferential therapy
in poisonings.
■ In neonates, CRRT has been used safely and effectively in treatment of hyperammonemia.
■ Recent study shows an effective role of CRRT in patients with acute fatty liver of pregnancy.

REFERENCES
1. Joannidis M. Continuous renal replacement therapy in sepsis and multisystem organ failure.
Semin Dial. 2009;22(2):160-4.
2. Atan R, Crosbie DC, Bellomo R. Techniques of extracorporeal cytokine removal: a systematic
review of human studies. Ren Fail. 2013;35(8):1061-70.
3. Ricci Z, Romagnoli S, Ronco C. High cut-off membranes in acute kidney injury and continuous
renal replacement therapy. Int J Artif Organs. 2017;40(12):657-64.
4. Bellomo R, Baldwin I, Cole L, et al. Preliminary experience with high-volume hemo-filtration in
human septic shock. Kidney Int Suppl. 1998;66:S182-5.
5. Borthwick EM, Hill CJ, Rabindranath KS, et al. High-volume haemofiltration for sepsis. Cochrane
Database Syst Rev. 2013:(1):CD008075.
6. Joannes-Boyau O, Honoré PM, Perez P, et al. High-volume versus standard-volume haemofiltration
for septic shock patients with acute kidney injury (IVOIRE study): a multicenter randomized
controlled trial. Intensive Care Med. 2013;39(9):1535-46.
7. Park JT, Lee H, Kee YK, et al. HICORES Investigators. High-dose versus conventional-dose
continuous venovenous hemodiafiltration and patient and kidney survival and cytokine removal
Chapter 15  Continuous Renal Replacement Therapy in Specific Situations/Diseases 117
in sepsis-associated acute kidney injury: a randomized controlled trial. Am J Kidney Dis.
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8. Forni LG, Ricci Z, Ronco C. Extracorporeal renal replacement therapies in the treatment of sepsis:
where are we? Semin Nephrol. 2015;35(1):55-63.
9. Atan R, Peck L, Visvanathan K, et al. High cut-off hemofiltration versus standard hemofiltration:
effect on plasma cytokines. Int J Artif Organs. 2016;39(9):479-86.
10. Malard B, Lambert C, Kellum JA. In vitro comparison of the adsorption of inflamma-tory mediators
by blood purification devices. Intensive Care Med Exp. 2018;6(1):12.
11. Schwindenhammer V, Girardot T, Chaulier K, et al. oXiris® Use in septic shock: experience of two
french centres. Blood Purif. 2019;47(Suppl 3):29-35.
12. Marenzi G, Grazi S, Giraldi F, et al. Interrelation of humoral factors, hemodynamics and fluid and
salt metabolism in congestive heart failure: effects of extracorporeal ultrafiltration. Am J Med.
1993;94(1):49-56.
13. Costanzo MR, Saltzberg M, O’Sullivan J, et al. Early ultrafiltration in patients with decompensated
heart failure and diuretic resistance. J Am Coll Cardiol. 2005;46(11):2047-51.
14. Bart BA, Boyle A, Bank AJ, et al. Ultrafiltration versus usual care for hospitalized patients with
heart failure. The Relief for Acutely fluid-overloaded patients with decompensated congestive heart
failure (RAPID-CHF) trial. J Am Coll Cardiol. 2005;46(11):2043-6.
15. Costanzo MR, Guglin ME, Saltzberg MT, et al. UNLOAD Trial Investigators. Ultrafiltration versus
intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll
Cardiol. 2007;49(6):675-83.
16. Wong CK, Pun KK, Cheng CH, et al. Hypocalcemic heart failure in end-stage renal disease. Am J
Nephrol. 1990;10(2):167-70.
17. Blake P, Hasegawa Y, Khosla MC, et al. Isolation of “myocardial depressant factor(s)” from the
ultrafiltrate of heart failure patients with acute renal failure. ASAIO J. 1996;42(5):M911-5.
18. Giglioli C, Spini V, Landi D, et al. Congestive heart failure and decongestion ability of two different
treatments: Continuous renal replacement and diuretic therapy: experience of a cardiac step down
unit. Acta Cardiol. 2013;68(4):355-64.
19. Premuzic V, Basic-Jukic N, Jelakovic B, et al. Continuous veno-venous hemofiltration improves
survival of patients with congestive heart failure and cardiorenal syndrome compared to slow
continuous ultrafiltration. Ther Apher Dial. 2017;21(3):279-86.
20. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC Committee for Practice Guidelines (CPG). ESC
guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: The task force
for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of
Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and
endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008;29(19):
2388-442.
21. Ortega LM, Ladino M. The use of continuous renal replacement therapy in sepsis, liver disease,
acute neurological injuries and decompensated heart failure. Dial Traspl. 2009;30(4):133-8.
22. Park CY, Choi HY, You NK, et al. Continuous renal replacement therapy for acute renal failure in
patients with traumatic brain injury. Korean J Neurotrauma. 2016;12(2):89-93.
23. Ronco C, Bellomo R, Brendolan A, et al. Brain density changes during renal replacement in
critically ill patients with acute renal failure. Continuous hemofiltration versus intermittent
hemodialysis. J Nephrol. 1999;12(3):173-8.
24. Fletcher JJ, Bergman K, Carlson G, et al. Continuous renal replacement therapy for refractory
intracranial hypertension? J Trauma. 2010;68(6):1506-9.
25. Laurent I, Adrie C, Vinsonneau C, et al. High-volume hemofiltration after out-of- hospital cardiac
arrest: A randomized study. J Am Coll Cardiol. 2005;46(3):432-7.
26. Davenport A, Roberts NB. Amino acid losses during continuous high-flux hemofiltration in the
critically ill patient. Crit Care Med. 1989;17(10):1010-4.
118 Section 1  Renal Replacement Therapy

27. Davenport A. Is there a role for continuous renal replacement therapy in patients with liver and
renal failure? Kidney Int Suppl. 1999;(72):S62-6.
28. Jalan R, O Damink SW, Deutz NE, et al. Moderate hypothermia for uncontrolled intracranial
hypertension in acute liver failure. Lancet. 1999;354(9185):1164-8.
29. Nitta M, Hirasawa H, Oda S, et al. Long-term survivors with artificial liver support in fulminant
hepatic failure. Ther Apher. 2002;6(3):208-12.
30. Cardoso FS, Gottfried M, Tujios S, et al. US Acute Liver Failure Study Group. Continuous renal
replacement therapy is associated with reduced serum ammonia levels and mortality in acute
liver failure. Hepatology. 2018;67(2):711-20.
31. Wong LP, Blackley MP, Andreoni KA, et al. Survival of liver transplant candidates with acute renal
failure receiving renal replacement therapy. Kidney Int. 2005;68(1):362-70.
32. Townsend DR, Bagshaw SM, Jacka MJ, et al. Intraoperative renal support during liver transplantation.
Liver Transpl. 2009;15(1):73-8.
33. McLean AG, Davenport A, Cox D. Effects of lactate-buffered and lactate-free dialysate in CAVHD
patients with and without liver dysfunction. Kidney Int. 2000;58(4):1765-72.
34. Morath C, Miftari N, Dikow R, et al. Sodium citrate anticoagulation during sustained low efficiency
dialysis (SLED) in patients with acute renal failure and severely impaired liver function. Nephrol
Dial Transplant. 2008;23(1):421-2.
35. Yessayan L, Yee J, Frinak S, et al. Continuous renal replacement therapy for the management
of acid-base and electrolyte imbalances in acute kidney injury. Adv Chronic Kidney Dis.
2016;23(3):203-10.
36. Levraut J, Ciebiera JP, Jambou P, et al. Effect of continuous venovenous hemofiltration with dialysis
on lactate clearance in critically ill patients. Crit Care Med. 1997;25(1):58-62.
37. Bouchard J, Roberts DM, Roy L, et al. Principles and operational parameters to optimize poison
removal with extracorporeal treatments. Semin Dial. 2014;27(4):371-80.
38. Bellomo R, Kearly Y, Parkin G, et al. Treatment of life-threatening lithium toxicity with continuous
arterio-venous hemodiafiltration. Crit Care Med. 1991;19(6):836-7.
39. Licari E, Calzavacca P, Warrillow SJ, et al. Life-threatening sodium valproate over-dose:
a comparison of two approaches to treatment. Crit Care Med. 2009;37(12):3161-4.
40. Spinale JM, Laskin BL, Sondheimer N, et al. High-dose continuous renal replacement therapy for
neonatal hyperammonemia. Pediatr Nephrol. 2013;28(6):983-6.
41. Yu CB, Chen JJ, Du WB, et al. Effects of plasma exchange combined with continuous renal
replacement therapy on acute fatty liver of pregnancy. Hepatobiliary Pancreat Dis Int.
2014;13(2):179-83.
CHAPTER 16
Nutrition during Renal Replacement Therapy
Khalid Ismail Khatib, Subhal Bhalchandra Dixit

INTRODUCTION
Nutrition in patients with acute kidney injury (AKI) plays an important part in the overall
treatment and well-being of the patient and it also plays an important part in the prognosis.
The metabolic abnormalities and the type of nutrition required vary with the type and severity
of the renal diseases, which lead to renal failure and the treatment initiated [intermittent
hemodialysis (HD) versus slow low-efficiency dialysis (SLED) versus continuous renal
replacement therapy (CRRT)].

SCREENING OF PATIENTS FOR MALNUTRITION RISK


This may be done using any of the following scores/tools. It should be assessed within the first
48 hours of hospitalization.
■ Nutrition risk in the critically ill (NUTRIC) score
■ Mini nutritional assessment (MNA)
■ Short nutritional assessment questionnaire (SNAQ)
■ Malnutrition universal screening tool (MUST)
■ Radiological tools include ultrasonography of quadriceps muscle (to measure muscle
mass and changes during course of illness) and CT scan analysis of skeletal muscle density
■ Nutritional risk screening-2002 (NRS-2002).
Patients are at high risk of malnutrition, if the NUTRIC score is ≤5 or NRS score is >3. MNA
score value of 0–7 points denotes malnourished individuals at start of the illness, while a score
of 8–11 points denotes individuals who may develop malnutrition.
In patients with AKI on renal replacement therapy (RRT), the International Society of Renal
Nutrition and Metabolism (ISRNM) prefers to call it “protein-energy wasting (PEW)” and it
is defined as a “state in which there is a reduction of body stores of both protein as well as
energy fuels.” This reduction in body protein and fat masses often leads to reduced functional
capacity.1
120 Section 1  Renal Replacement Therapy

The malnutrition inflammation score (MIS) has been developed and studied. It has a
better association with hospital admission of the patients and with their mortality. It is also
associated with nutritional and inflammatory parameters in AKI patients.2 It is also known as
Kalantar Score.

ASSESSMENT OF NUTRITION
Nutrition can be assessed by various tools used in combination, as no single tool gives the best
assessment. The following tools can be used for assessment of nutrition in patients on RRT
(Table 1).3 The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF
KDOQI) recommends assessment of serum albumin and actual body weight every month,
while subjective global assessment (SGA) may be measured every 6 months, in patients
undergoing RRT.4

Table 1: Tools used for assessment of nutrition in patients undergoing renal replacement therapy.
Tools Calculation Comments
Anthropometry Simple, inexpensive, and can be performed
at the patient bedside
Percentage weight loss It is calculated as [(current weight/ Significant if >5%, 7.5%, and 10% at 1, 3,
usual weight) –1 × 100] and 6 months, respectively
Body mass index (BMI) It is calculated by the formula: BMI <20 is associated with high mortality
Weight in kilogram divided by the
(height in meters)2
Skin fold thickness (SFT) Measured at biceps, triceps, Measured using skin fold calipers
subscapular region, and iliac crest. It
is calculated as the mean of at least
three measurements
Mid-arm circumference Measured at midpoint of the line Measured in nondominant upper limb and
(MAC) joining acromion and olecranon in patients with arteriovenous fistula in the
processes nonfistula arm
Subjective global Takes into account the following Patients classified as well-nourished
assessment (SGA) points—visual assessment of and according to the severity of
subcutaneous fat and muscle mass, malnourishment as moderately or severely
anorexia, functional capacity, GI malnourished. Correlates well with
symptoms, and weight loss over prognosis
6 months
Biochemistry: Serum Measured using bromocresol green, Simple, widely available. Lower values
albumin/Prealbumin cellulose acetate electrophoresis, or associated with poor prognosis. But, it is an
sodium sulfite precipitation/biuret unreliable indicator of nutritional status as
methods its value depends on many variables.
Others Not widely and easily available
(X-ray absorptiometry,
bioelectrical impedance,
near infrared)
(GI: gastrointestinal)
Chapter 16  Nutrition during Renal Replacement Therapy 121

Estimation of Nutritional Requirements5,6


Nutritional requirements in patients on RRT may be estimated using predictive equations
(Harris–Benedict, Ireton-Jones, Penn State, Mifflin-St Jeor, etc.) or by indirect calorimetry.

ROUTE FOR NUTRITION IN PATIENTS WITH ACUTE KIDNEY INJURY ON


RENAL REPLACEMENT THERAPY
Reduced oral intake in patients with AKI on RRT can be improved by treating gastroparesis
or other gastrointestinal conditions, if present, treating associated depression, correcting
electrolyte abnormalities, and achieving glycemic control.7 Diet should be low in potassium
and phosphates. Vitamin D supplementation may be required.

Oral Nutritional Supplementation


Patients with AKI on RRT who are able to take orally should receive oral nutritional supplements
(ONS). The frequency of administration should be 2–3 times in 24 hours. ONS provides
approximately additional 7–10 kcal per kg per 24 hours of energy. It also provides 0.3–0.4 g of
protein per kg per 24 hours. ONS improves serum albumin levels. It also leads to improvement
in nutritional status.8

Enteral Feeding
Patients who are not able to take adequate protein and energy, so as to meet their daily targets
(with/without ONS) may be considered for enteral feeding with the placement of nasogastric
tube/nasojejunal tube. Enteral feeding is especially useful in patients with stroke and critically
ill patients.9,10 The type of enteral diet used in these patients should be polymeric (nephro)
diets (ready-to-use liquid preparations) with not very high or very low protein content and less
amount of electrolytes (potassium, phosphorus). There may be inclusion of other substances
like carnitine.10

Parenteral Nutrition
Supplemental or total parenteral nutrition is rarely required. It may be needed in those
patients who cannot take adequate amount of calories or proteins enterally or those unable to
tolerate enteral feeds. All-in-one bags may be used with special attention to total fluid given
and electrolyte content of the used formula.

A PRACTICAL APPROACH TO A PATIENT OF ACUTE KIDNEY INJURY


UNDERGOING RENAL REPLACEMENT THERAPY
The nutritional requirement of AKI patients will vary according to the type of RRT they are
undergoing. The nutritional losses during RRT depend on the type of RRT, whether HD or CRRT.
Also it depends on the type of dialysate and the membrane used. This is especially important
in protein requirement and electrolyte supplementation. Also carbohydrate requirements
should factor in additional carbohydrates present in intravenous maintenance fluids (like
122 Section 1  Renal Replacement Therapy

lactate, glucose or citrate). There are carbohydrates present in the dialysate or hemofiltration
fluids, which need to be factored in. Follow the below steps in deciding the nutrition plan in
AKI patients undergoing RRT:
■ Calculate the total energy requirement: The ideal energy target for AKI patients undergoing
RRT is 35 kcal per kg per day.4 But a more practical and achievable target is 80% of the ideal
requirement.11 A 60-kg patient who develops AKI and is undergoing CRRT should ideally
receive 2,100 kcal of total energy in a day.
■ Calculate protein requirement: The AKI patient not on RRT will require 0.6–1 g per kg ideal
weight per day of protein while those on intermittent HD will require more protein to
combat the loss of amino acids and protein during the procedure (1.2–1.5 g per kg ideal
body weight per day). Those undergoing CRRT and/or have other hypercatabolic states
(i.e. those with severe sepsis, etc.), will require even higher amount of proteins (1.7–2.5 g
per kg ideal body weight per day).4
The higher requirement for patients on RRT is due to loss of amino acids and proteins
during the procedure. For every 5 liters of filtrate in CRRT, 1 g of protein is lost. These losses
may be even more with certain types of dialyzer membranes.12 It is therefore important to
deliver the higher requirement in these patients to prevent nutritional deficit.
A 60-kg patient, not on RRT, will require 36–60 g of protein in a day while the same patient
if undergoes intermittent HD will require 72–90 g protein/day and if undergoes CRRT will
require 102–150 g protein/day.
■ Calculate carbohydrate requirement: About 50–60% of total energy requirement should be
provided by carbohydrates. Care should be taken to include all the carbohydrates given to
the patient, including that present in intravenous fluids and the solutions used in different
types of RRT. Hyperglycemia should be combated by use of intensive insulin protocol,
albeit cautiously.4,13 These patients may be more prone to hypoglycemia as approximately
30–35% of insulin is metabolized in the kidneys (which is decreased in patients with AKI).14
■ Calculate lipid requirement: It should be 30–35% of total energy requirement and
0.8–1.2 g per kg per day. Thus, a 60-kg patient will require 48–72 g per day. As patients
with AKI are prone to hypertriglyceridemia, it has been proposed to use medium- and
long-chain-containing lipids to prevent it.14
■ Calculate total fluid intake allowed for 24 hours: As the condition of the critically sick patients
may vary throughout the day, the estimation of fluid requirement may have to be done
several times. Roughly, 1,000 mL plus urine output (if any) should give the approximate
maintenance fluid allowed in a day. Comorbidities like cardiac failure or fluid overload or
even hypovolemia (due to any reason) may have to be factored in this decision. Colloids
(dextran or hydroxyethyl starch) should be avoided.15
■ Calculate micronutrients requirement: Doses need to be carefully calibrated as some
micronutrients are lost during RRT and hence require higher doses while others may
accumulate and have adverse effects. Calcium and magnesium are depleted in citrate
CRRT while potassium and phosphate are lost in all CRRT.
Sodium: 2 g every 24 hours.
Potassium: 2–3 g every 24 hours.
Chapter 16  Nutrition during Renal Replacement Therapy 123
Phosphorus:16 One has to be careful in deciding the dose of phosphorus in patients on RRT.
10–15 mg per kg per day (0.6–1 g every 24 hours for a 60 kg person) would be ideal. The higher
dose is required in critically ill patients on RRT for a longer time as hypophosphatemia is
prevalent in these patients. This may even lead to the refeeding syndrome. This dose should
not be exceeded as it may lead to hyperphosphatemia.
Vitamins and trace elements:
■ Vitamin B complex:
– Thiamine: 25–100 mg/day (lower doses in HD patients and higher doses in patients
undergoing CRRT)
– Folate: 1 mg/day (approximately 25% lost in CRRT)
– Pyridoxine: 10 mg/day.
■ Vitamin A: (not more than 700–900 μg/day) Patients of AKI given more vitamin A may
develop hypervitaminosis as plasma vitamin A levels are elevated due to decreased
destruction of plasma retinol-binding protein in the diseased kidney.
■ Vitamin C: (100 mg/day in patients undergoing intermittent HD; up to 200 mg/day in
patients undergoing CRRT) It should be supplemented. The higher requirement in CRRT is
due to the fact that approximately half of vitamin C is lost in ultrafiltrate. Kindly remember
that vitamin C is converted to oxalate, which is one of the toxins which accumulate in
uremia and is also renal toxic.11,12,14
■ Vitamin D:17,18 Recent research has demonstrated association of vitamin D with various
adverse outcomes in critically ill patients. A high dose of 60,000 international units of
25-hydroxy-vitamin D for 2 doses may be given to these patients.
■ Zinc: Zinc may not need to be supplemented as CRRT replacement fluid and citrate
anticoagulant contains zinc. In other RRT, use normal doses.
■ Selenium: 100 μg/day in patients on CRRT (one and half times the normal daily dose in
other patients).
■ Copper: 300–500 μg/day as almost 80% is lost in CRRT. However, patients with jaundice and
AKI should not receive copper supplementation.

CONCLUSION
Patients on RRT require special attention to their nutritional requirements.
Assessment of nutritional risk is important and must be carried out within 48 hours of
hospitalization.
Every effort should be made to attain energy and protein requirement targets.
Measures to improve oral intake, use of ONS, enteral and parenteral feeding, in selected
patients, lead to overall improvement in morbidity and mortality.

REFERENCES
1. Fouque D, Kalantar-Zadeh K, Kopple J, et al. A proposed nomenclature and diagnostic criteria for
protein-energy wasting in acute and chronic kidney disease. Kidney Int. 2008;73(4):391-8.
2. Kalantar-Zadeh K, Kopple JD, Block G, et al. A malnutrition-inflammation score is correlated with
morbidity and mortality in maintenance hemodialysis patients. Am J Kidney Dis. 2001;38(6):1251-63.
124 Section 1  Renal Replacement Therapy

3. Kalantar-Zadeh K, Fouque D. Nutritional management of chronic kidney disease. N Engl J Med.


2017;377(18):1765-76.
4. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO
clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2:1-138.
5. Beto JA, Bansal VK. Medical nutrition therapy in chronic kidney failure: integrating clinical practice
guidelines. J Am Diet Assoc. 2004;104(3):404-9.
6. McClave SA, Taylor BE, Martindale RG, et al.; Society of Critical Care Medicine, American Society
for Parenteral and Enteral Nutrition. Guidelines for the provision and assessment of nutrition
support therapy in the adult critically III patient: Society of Critical Care Medicine (SCCM) and
American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr.
2016;40(2):159-211.
7. Parrish CR. Nutrition in renal failure: myths and management. Pract Gastroenterol. 2004;20:40-59.
8. Kalantar-Zadeh K, Cano NJ, Budde K, et al. Diets and enteral supplements for improving outcomes
in chronic kidney disease. Nat Rev Nephrol. 2011;7(7):369-84.
9. Fouque D, Vennegoor M, Ter Wee P, et al. EBPG guideline on nutrition. Nephrol Dial Transplant.
2007;22 Suppl 2:ii45-87.
10. Druml W. Basics in clinical nutrition: nutritional support in renal disease. e-SPEN, the European
e-Journal of Clinical Nutrition and Metabolism. 2010;5:e54-7.
11. Gervasio JM, Cotton AB. Nutrition support therapy in acute kidney injury: distinguishing dogma
from good practice. Curr Gastroenterol Rep. 2009;11(4):325-31.
12. McCarthy MS, Phipps SC. Special nutrition challenges: current approaches to acute kidney injury.
Nutr Clin Pract. 2014;29(1):56-62.
13. Singer P, Berger MM, Van den Berghe G, et al.; ESPEN. ESPEN guidelines on parenteral nutrition:
intensive care. Clin Nutr. 2009;28(4):387-400.
14. Fiaccadori E, Parenti E, Maggoire U. Nutritional support in acute kidney injury. J Nephrol.
2008;21(5):645-56.
15. Lameire NH, Bagga A, Cruz D, et al. Acute kidney injury: an increasing global concern. Lancet.
2013;382(9887):170-9.
16. Cano NJ, Aparicio M, Brunori G, et al. ESPEN guidelines on parenteral nutrition: adult renal failure.
Clin Nutr. 2009;28(4):401-14.
17. Massey K, Dickerson RN, Brown RO. A review of vitamin D deficiency in the critical care population.
Pharmacy. 2014;2:40-9.
18. Amrein K, Venkatesh B. Vitamin D and the critically ill patient. Curr Opin Clin Nutr Metab Care.
2012;15(2):188-93.
CHAPTER 17
Drug Dosing in Continuous Renal
Replacement Therapy
Ranajit Chatterjee, Priyanka H Chhabra

Continuous renal replacement therapy (CRRT) is the modality of choice1,2 for critically ill
patients developing severe renal dysfunction and hemodynamic instability. It is also required
in patients with acute liver failure, cerebral edema, severe metabolic acidosis, and electrolyte
imbalances, and in patients of sepsis and hypercatabolism, as a modality to deresuscitate
in certain poisonings, to name a few. Drug dosing in such patients can be very challenging.
The convective therapy added to the regular diffusive therapy along with a large absorptive
membrane makes the dosing process even more complex. As most of the drugs, apart from
antibiotics, can be titrated to its effect; this chapter will be restricting itself to dosing of antibiotics
during CRRT.
Antibiotic dosing in CRRT is basically a fight between underdosing and overdosage.3
Three important points make the assessment of antimicrobial dosing important in critically
ill patients. First of all, antibiotics are the most important and commonly prescribed drugs
in critically ill. Secondly, they cannot be titrated to effect as changes in clinical markers
usually occur over days. Third and the most important of all, underdosing of these essential
medications is more dangerous than overdosage.
Renal failure can pose challenges in optimum antibiotic therapy. Appropriate dosing is of
paramount importance as routine doses in renal failure patients can lead to toxicity,4 whereas
suboptimal levels can lead to treatment failure and spread of resistance.

PHARMACOKINETIC PARAMETERS
The effect of antibiotics depends on its absorption, distribution, metabolism, and elimination,
which in turn depends on the existing renal and liver function. In addition, in critically
ill patients, there is altered hemodynamics, hydration state, and failing organ support
compounded with the different drug interactions, and also the different modalities of therapy
[continuous venovenous hemofiltration (CVVHF) continuous venovenous hemodiafiltration
(CVVHDF), continuous venovenous hemodialysis (CVVHD)] which make the whole process
complicated.
Various factors influence drug dosing in patients receiving CRRT. They are listed in Table 1.
126 Section 1  Renal Replacement Therapy

Table 1: Factors which influence drug dosing in patients receiving CRRT.


Drug factors Patient factors Dialysis factors
Plasma protein binding capacity Residual renal function Dialysis type (CRRT/SLED/IHD/PD)
Volume of distribution Alterations in Vd Membrane pore size/sieving coefficient
Hydrophilicity/lipophilicity Alterations in plasma Blood and dialysate flow, ultrafiltration
protein binding
Clearance Mechanism of solute transfer (Diffusion/
convection)
(CRRT: continuous renal replacement therapy; IHD: intermittent hemodialysis; PD: peritoneal dialysis; SLED:
sustained low efficiency dialysis)

DRUG FACTORS
Plasma Protein Binding
It determines the amount of free fraction of a drug, which is the physiologically active form.
Drugs with high plasma protein binding form large molecular weight (drug protein)
complexes which are seldom removed by dialyzer membranes (teicoplanin and clindamycin),
whereas less plasma protein-bound drugs are easily dialyzed.

Volume of Distribution
It is a conceptual volume that drug would occupy if body were a single homogeneous
compartment.
Vd = Amount in the body/plasma concentration.
Drugs with low Vd remain confined to the vascular compartment and are readily dialyzed.
On the other hand, drugs with high lipid solubility (and Vd) often penetrate the tissues, which
makes them difficult to be removed by dialysis.

Hydrophilicity/Lipophilicity
Hydrophilic antibiotics (β-lactams, aminoglycosides, and glycopeptides) have small volume
of distribution and renal clearance, compared to the lipophilic antibiotics (fluoroquinolones,
macrolides, tetracycline, chloramphenicol, and rifampicin) that have large volume of
distribution and hepatic clearance.
It is of clinical significance for the calculation of loading dose because plasma levels
following loading dose depends primarily on the volume of distribution (Vd).

Clearance
It is a measure of the ability of body to eliminate a drug.
Maintenance dose of a drug depends on clearance at steady state.
Sepsis often leads to increased volume of distribution, decreased renal clearance (due to
dysfunction), and altered plasma protein binding. Table 2 summarizes the determinants of
drug removal during CRRT.
Chapter 17  Drug Dosing in Continuous Renal Replacement Therapy 127

DIALYSIS FACTORS
Membrane Pore Size (Sieving Coefficient)
Capacity of a drug to sieve through a high-permeability dialyzer membrane is called as sieving
coefficient (SC).
SC = Cf/Cp
Cf = Drug concentration in filtrate
Cp = Drug concentration in plasma.
Large membrane pore size allows passage of medium and large molecular weight drugs to
be removed by dialysis.

Blood and Dialysate Flow


Increase in both blood and countercurrent dialysate flow results in increased drug clearance.

Diffusion versus Convection


Convective therapy (CVVHF and CVVHDF) will remove antibiotics of higher molecular
weights (vancomycin and teicoplanin), when compared to diffusive therapies like CVVD.
Hence, the doses of these drugs have to be increased when a convective therapy is performed.
Table 3 illustrates the comparison of pharmacokinetics of IHD and CRRT.

Table 2: Determinants of drug removal during CRRT.


Drug Filter CRRT
Degree of renal elimination Material CVVH/CVVHD/CVVHDF
Protein binding Composition Duration
Vd Surface area Blood flow
Molecular weight Permeability Ultrafiltrate flow
Drug charge Dialysate rate
Pre-/postdilution
(CRRT: continuous renal replacement therapy; CVVHDF: continuous venovenous hemodiafiltration;
CVVHD: continuously venovenous hemodialysis; CVVH: continuous venovenous hemofiltration)

Table 3: Comparison of pharmacokinetics, IHD vs CRRT.


IHD CRRT
Elimination by RRT limited to treatment time, e.g. Nearly continuous elimination by CRRT
HD 3–4 hr/week, supplemental doses are required
following dialysis
Significant dose reductions of drug predominantly Often only slight reduction of normal drug dosing,
cleared by kidney is warranted sometimes dose increase is also required
Sufficient recommendation of dose based on chronic Reliable dose recommendation often missing
dialysis data
(CRRT: continuous renal replacement therapy; HD: hemodialysis; IHD: intermittent hemodialysis; RRT: renal
replacement therapy)
128 Section 1  Renal Replacement Therapy

DRUG DOSING CONSIDERATIONS


General Principles
Drug dosing in CRRT may be based on the following methods:
1. Clinical studies
2. Total creatinine clearance approach
3. Therapeutic drug monitoring
4. Dose as if the creatinine clearance = 20–50 mL/min.

Loading Dose
In general, the loading dose should be kept unchanged, especially for water-soluble drugs
which have small volume of distribution (<0.7 L/kg). The loading dose is calculated based on
ideal body weight plus the weight gained from volume overload (weight change from baseline
weight during admission).
Loading dose can be calculated as follows:
Cp × Vd
F×S
Where
Cp = Desired peak concentration of drug
Vd = Volume of distribution of drug
F = Bioavailability
S = Salt fraction
So, drugs whose volume of distribution are increased, will have to be given a higher loading
dose, like the cephalosporins, β-lactams, and the penems.

Maintenance Dose
The maintenance dose should be adjusted only for drugs with the following properties:
■ >50% renal excretion, low rate of protein binding, and small volume of distribution.
■ The maintenance dose can be altered either by changing the dose or duration. It can be
calculated by the following formula:
– Dosing interval [for concentration dependent antibiotics, Cmax/Minimum inhibitory
concentration (MIC)]:
Normal CLCR
× Normal interval
Patient’s CLCR
– DOSE (for time-dependent antibiotics T > MIC):
Patient’s CLCR
× Normal dose
Normal CLCR
The creatinine clearance can also be calculated by the following formula:
– Glomerular filtration rate (GFR) = TOTAL ClCR
= Endogenous ClCR + extracorporeal ClCR
Chapter 17  Drug Dosing in Continuous Renal Replacement Therapy 129
(140−Age) × lean body weight
ClCR = × (0.85)
72 × Serum creatinine
Extracorporeal ClCR = UF rate (mL/min)
1440
Note: If predilution replacement fluid is given, then the dilution factor has to be multiplied
with the extracorporeal creatinine clearance.
If concentration of drug can be calculated, then drug removal can be calculated from the
following formula:
Drug removal (mL/min) = [ClrenalClhepatic+Clcrrt] × concentration (mg/mL)
T1/2 = 0.693 × Vd/Cltot
■ Drugs with no renal clearance do not need any dose adjustment.
■ Drugs whose renal clearance is >25% of total clearance, or which have active metabolites
excreted through the kidneys, need dose adjustment.
However, many a times, the formulae calculating the dose of antibiotics in RRT, and
especially CRRT has been found to be inaccurate.

Limitations
The total creatinine clearance approach has limitations. Serum creatinine is generated from
muscle mass and diet. So, elderly patients with reduced muscle mass often have reduced serum
creatinine values; on the other hand, patients with amputation have higher values. Similarly,
patients on vegan diet have reduced creatinine levels whereas those patients on red meat diet
have higher values. This is the major limitation in using serum creatinine for estimation of
GFR. It cannot be rectified by making any adjustment in the formula.
It ignores tubular drug handling. The actual effect of HF on drug clearance might
be overestimated for drugs with a high tubular secretion (β-lactam antibiotics) and
underestimated for drugs for which considerable tubular absorption takes place (fluconazole).
Hence, dosing based on therapeutic drug monitoring (TDM) is by far the best method for
determination of drug doses in CRRT. It is the most reliable method, and is mandatory for
drugs with a narrow therapeutic index. The exact information on the given dose, time of
administration and CRRT is essential. However, this method is scarcely available in most of
the centers.

Individual Antimicrobial Agents


Patients with chronic kidney disease (CKD) frequently require antibiotics for the management
of infections. Optimum dosing is the key to successful management. Various physiological
changes that take place in CKD are responsible for variations in drug dosing.
For orally administered agents, bioavailability is reduced due to bowel wall edema, delayed
peristalsis and frequent use of phosphate binders.
Parenteral antibiotics also require dosage modification. Loading dose remains the same
but maintenance doses are given in lesser amounts and at longer intervals (due to reduced
renal clearance) (Box 1).
130 Section 1  Renal Replacement Therapy

Box 1: Drugs which do not require any dose modification.


• Amphotericin B
• Azithromycin
• Ceftriaxone
• Clindamycin
• Doxycycline
• Linezolid
• Metronidazole
• Rifampicin
• Tigecycline
• Voriconazole

β-lactams
These are small hydrophilic molecules with low Vd, which renders them readily dialyzable.
They exhibit time-dependent killing, i.e. bactericidal activity is dependent on the amount
of time. During dosing interval, their levels remain above MIC (%t >MIC). Generally, it is
recommended that they should be given by standard dose during first 48 hours of initiation
of therapy and thereby, dose adjustment to be individualized as per renal function and
patient parameters.
Imipenem is administered with cilastatin to reduce metabolism via renal
dehydropeptidase-1. In order to maintain adequate trough concentrations, a dosage of 250 mg
q 6 hr or 500 mg q 8 hr is required. Cilastatin gets accumulated in hepatic dysfunction, thus
demanding increase in dosing interval.
Meropenem is a low-molecular weight molecule with low Vd and less plasma protein binding
capacity. These features make meropenem, a readily dialyzable drug.5 The recommendations
regarding maintenance dose are 500–1,000 mg every 12 hours or 8 hours.
Piperacillin-tazobactam dosage of 2.25 g q 6 hr6 produces adequate antibiotic concen-
trations in blood in patients receiving CRRT. However, for treating relatively drug-resistant
bacteria like Pseudomonas aeruginosa, a higher dose of 3.375 g q 6 hr is required.
An exception is ceftriaxone, which undergoes biliary (nonrenal) elimination and does not
require any dose modification.

Vancomycin
It is a middle-molecular weight antibiotic, but is effectively removed by CVVHDF and CVVHD.
It is required to be given at a dose of 15–20 mg/kg (loading dose), followed by a maintenance
dose of 500 mg q 24 hr–1,500 mg q 48 hr.7 It is prudent to measure serum vancomycin levels for
optimum dosing of the drug. For skin and soft-tissue infections and uncomplicated bacteremia,
an optimal trough concentration of 5–10 mg/dL is needed. Higher vancomycin levels (trough
concentration of 10–15 mg/dL) are also required for infections where deeper penetration into
body tissues is desired like bones and meninges. In healthcare-associated pneumonia, due to
suboptimal penetration of vancomycin in lung tissues, a much higher trough concentration of
15–20 mg/dL is necessary.
Chapter 17  Drug Dosing in Continuous Renal Replacement Therapy 131

Linezolid
About 30% of the dose is excreted in the urine as unchanged drug. Therefore, no dose
adjustment is required in patients with deranged renal function. It is recommended to be
given in usual dose of 600 mg q 12 hr.

Teicoplanin
Loading dose (400 mg 12 hour for 3 doses) remains the same in patients on CRRT. For patients
with creatinine clearance < 10 mL/min, a dose of 200–400 mg every 48–72 hours.

Aminoglycosides
Aminoglycoside pharmacokinetics is characterized by concentration-dependent killing
(Cmax/MIC) and a significant postantibiotic effect (>3 hour). Cmax/MIC ratio of 8–10 is
recommended.8 It is recommended that optimal aminoglycoside dosing includes higher doses
given as a single dose. It is also recommended to monitor drug levels of aminoglycosides daily,
if used in divided doses, and every 48 hours, if used in a single dose. This helps in reducing
aminoglycoside toxicity and extends the postantibiotic effect (PAE). The loading dose is
increased, if there is increase in artificial clearance.8

Fluoroquinolones
Quinolones are highly lipophilic antimicrobial agents, which undergo concentration-
dependent killing. Like aminoglycosides, they also require high initial loading dose for
optimum antibacterial action.
Ciprofloxacin, a dose of 600–800 mg/day is recommended.9
Levofloxacin is excreted unchanged in urine and requires dose adjustment in patients with
renal dysfunction. A loading dose of 500 mg followed by 250 mg q 24 hr is appropriate for
patients undergoing CRRT.9
Moxifloxacin dosage remains unaltered owing to biliary excretion.
Both ciprofloxacin and levofloxacin have significant levels of adsorption to the membranes,
so a higher dose is recommended particularly when convective therapy is performed.

Colistin
Colistin is the last-resort antibiotic in treating drug-resistant bacteria in clinical practice. Precise
dosing is required to avoid colistin resistance amongst the human race.
Colistin is a narrow-spectrum antibiotic against gram-negative bacteria, concentration-
dependent, rapid bactericidal effect, with a very modest PAE against P. aeruginosa. It is
available as colistin methanesulfonate (CMS) (prodrug) in parenteral formulation. CMS gets
converted to colistin in body slowly; hence, it should always be given with a loading dose.
MIC breakpoint to identify bacteria susceptible to colistimethate sodium is <mg/L. MIC > 8
mg/L should be considered resistant. During infective states, colistin is bound to alpha-1-acid
glycoprotein (>95%). Colistin gets adsorbed to the highly adsorptive surface of AN 69 membrane
and around 85% of colistin is removed. This is augmented by regional citrate anticoagulation.
132 Section 1  Renal Replacement Therapy

As adsorption is bulk related, there is no significant saturation and consequently no significant


side effect is seen even with a higher dose of colistin. The loading dose of 9 million units in 100
mL normal saline (NS) over 30 minutes should be given followed by a maintenance dose of
4.5 million units twice-a-day if creatinine clearance is >50 mg/mL. The dose duration is to be
increased with decreasing creatinine clearance. However, due to increased CRRT clearance
the current loading dose might be suboptimal, especially in presence of sepsis syndromes.
Dosage of 2.5 mg/kg q 48 hr in patients undergoing CRRT is recommended.9

Polymyxin B
Polymyxin B is also among one of the last resort antibiotics primarily due to its action against
multidrug-resistant (MDR) gram-negative bacteria. It undergoes clearance mainly via
nonrenal mechanisms; hence, dose adjustment is usually unnecessary: 15,000–25,000 U/kg/
day q 12 hr.10,11

Antifungals
Azole antimycotics are widely used for systemic fungal infections. Fluconazole undergoes
concentration-dependent kinetics, hence optimum dosage is dependent on AUC/MIC ratio.
Fluconazole is excreted largely unchanged in urine and has elimination T1/2 of 25–35 hours.
It also undergoes reabsorption in kidneys to a large extent. It, therefore, requires dosage
modification in patients on CRRT.12 The dosage of 800 mg/day is appropriate in patients
undergoing CRRT. On the other hand, itraconazole and voriconazole are largely metabolized
in body and do not require any dose modification. However, voriconazole should be given
orally as parenteral formulation contains cyclodextrins, which are eliminated via kidneys and
can accumulate.
Echinocandins like caspofungin, anidulafungin are metabolized by nonrenal pathways
and hence, do not require any dose modification in patients undergoing CRRT.13
Amphotericin B (AMB) liposomal or colloidal dispersion have very large volume
of distribution and does not require dose modification in patients undergoing CRRT14
3–6 mg/kg IV.

Antivirals
Acyclovir is a small hydrophilic molecule, which is excreted primarily by kidneys; so it
requires dose modification in patients with renal function derangement. A dosage range of
5–7.5 mg/kg is recommended. A higher dose end of the range is usually apt for patients with
central nervous system (CNS) infections.11

Antibiotic use in Intermittent Hemodialysis


Intermittent hemodialysis (IHD) is still the most common form of renal replacement method
used in critically ill patients.15 Drug removal by IHD is dependent on many factors like plasma
protein binding, volume of distribution, molecular size, water solubility, and plasma clearance.
Dialysis procedure often affects drug clearance—filter pore size, ultrafiltration rates, and
Chapter 17  Drug Dosing in Continuous Renal Replacement Therapy 133
duration of dialysis procedure. Antibiotic dosing can be done either at the end of dialysis or in
the last hour of dialysis session. Administering antibiotics in last hour is beneficial as it aids in
removal of excess fluids, better intravenous access is available and also unnecessary delays in
giving antibiotics is avoided.

β-lactams
Since they exhibit time-dependent pharmacodynamics, dose adjustments in renal disease
require reduction in dose while maintaining the dosing interval. This ensures an adequate
period of time their drug levels are well above the MIC. Improper dose adjustment in CKD
patients along with reduced plasma protein binding can lead to changes in cerebrum leading
to myoclonus, convulsions and confusion.16 Tubular secretion also accounts for dosing
difficulties. Therefore, recommendations in renal patients should always be individualized.
Common side effects include hypersensitivity, platelet aggregation defect, and acute kidney
injury (AKI) (when used with vancomycin).16 Cephalosporins have enhanced activity against
gram-negative bacteria. Ceftazidime can be given 1 g on starting the therapy and then 1 g three
times a week after a session of IHD. This regimen ensures ceftazidime concentrations above
MIC for more than 45% of the dosing interval.

Vancomycin
Vancomycin is the drug of choice for the treatment of methicillin-resistant Staphylococcus
aureus (MRSA). Earlier, vancomycin was given in a dose of 15 mg/kg every 7–10 days as it was
considered that being a middle-molecular weight drug it is not removed during dialysis. But
nowadays with the use of high-flux filters, it is given thrice weekly (standard regimen).17

Aminoglycosides
Aminoglycosides are bactericidal agents with concentration-dependent pharmacodynamics.
High dose with extended interval seems to be an optimal dosing method. Therapeutic drug
monitoring is recommended to prevent their toxicity. Gentamicin is recommended in a dose
of 7 mg/kg IV once a day. This also prolongs the postantibiotic effect.

Fluoroquinolones
Fluoroquinolones have high oral bioavailability and excellent tissue penetration. With the
exception of moxifloxacin, all quinolones require dose adjustment in renal failure. Side effects
include peripheral neuropathy, QT interval prolongation, and tendon rupture.

Antibiotic use in Sustained Low Efficiency Dialysis


Sustained low efficiency dialysis (SLED) is a hybrid dialysis modality between IHD and CRRT,
utilizing blood and dialysate flow rates between 100 mL/min and 300 mL/min. It is easy to
use, has improved hemodynamic stability, does not require a separate dialysis machine, and is
less expensive. Since drug removal occurs primarily via diffusion, it favors removal of solutes
with low molecular weights. Antibiotics which require dosage modification in patients with
134 Section 1  Renal Replacement Therapy

SLED are those having high renal clearance, high water solubility, and low molecular weights.
Hence, these agents will often require adjustment of doses or administering usual doses after
dialysis.18

Carbapenems
Carbapenems are readily cleared via SLED. Ertapenem and meropenem differ in their
pharmacokinetic properties. Half-lives of meropenem and ertapenem are 1 and 4 hours,
respectively. Doripenem and imipenem have similar pharmacokinetic properties as
meropenem. Meropenem is recommended in a dose of 500–1000 mg every 8 hourly.17
Doripenem dose of 1,000 mg once daily is recommended.19

Quinolones
Dialysis dosing of these agents differ as per their pharmacokinetics. Whereas moxifloxacin
has primarily hepatic, ciprofloxacin has both renal and hepatic, levofloxacin has only renal
elimination. Hence, moxifloxacin does not require any dose modification and is administered
in usual dosage of 400 mg once a day. Owing to greater renal elimination, it is recommended
that levofloxacin should be given in a dose of 250–500 mg every 24–48 hours, depending on
disease severity.18 Ciprofloxacin is usually advised to be given at 400 mg every 24 hours.

Aminoglycosides
Aminoglycosides should be given as an initial loading dose followed by a maintenance dose on
the basis of measured plasma concentrations.

Colistin
In patients with SLED of 9 hours, it is recommended to be given at a dose of 9 million units per
day in three divided doses.20

Peritoneal Dialysis
Peritoneal dialysis (PD) uses peritoneum as the membrane to clear blood of the solutes. It can
be used to remove toxins and excess fluid from patient’s body. Table 4 illustrates the various
types of peritoneal dialysis with description.

Table 4: Types of peritoneal dialysis and their description.


S. No. Types of peritoneal dialysis Description Regimen
1. CAPD (continuous ambulatory Dialysis solution dwells 24 Day—3–4 exchanges in 4–6 hours
peritoneal dialysis) hours a day and exchanges Night—1 exchange in 10–12 hours
are done manually
2. CCPD (continuous cyclic Dialysis solution dwells for 24 Day—2 L of dialysate
peritoneal dialysis) hours and some exchanges Night—4 exchanges
are done by a cycler
3. NIPD (nocturnal intermittent Dialysis is done overnight with Day—No exchanges
peritoneal dialysis) cycler Night—6–8 exchanges
Chapter 17  Drug Dosing in Continuous Renal Replacement Therapy 135
Factors affecting drug removal in PD:
■ Capillary blood flow in the membrane
■ Patients residual renal function
■ Dwell time
■ Temperature and volume of dialysate
■ Molecular weight of drug
■ Plasma protein binding
■ Volume of distribution of drug.

Aminoglycosides in Peritoneal Dialysis


Gentamicin/tobramycin—they are given in a dose of 0.6 mg/kg BW/bag dialysate.
Amikacin—2 mg/kg dialysate in intermittent PD. While in continuous PD, 8 mg/L of
dialysate is given in loading dose and 4 mg/L in maintenance dose.
Vancomycin—its dosage is similar as in IHD. It is given 15–30 mg/kg intraperitoneal (IP)
every 5–7 days.

Penicillins and Cephalosporins in Peritoneal Dialysis


Very scarce data is available of its use in PD patients. Based on few studies, it is recommended to
be given in a dose of 2 g or 1 g every 12 hours for intermittent PD, while for continuous variant,
a dose of 75–100 mg/L is found to be sufficient.21 Meropenem 1 g daily is recommended for use
in intermittent PD patients (Table 5).

Table 5: Drug dosing consideration in patients with acute and chronic kidney disease—A clinical
update from Kidney Disease: Improving Global Outcomes (KDIGO) 2011.
Drug dosing concerns in • Clinicians should use the most appropriate tool to assess renal function
patients with CKD for individual patient (i.e. measured vs estimated)
• Clinical laboratories should also report eGFR in mL/min
• Drug dosages should be adjusted according to FDA- or EMA-approved
product labeling
• When there is no information in the product label, peer-reviewed
literature recommendations should be used to guide drug dosage
regimen adjustments
• Obese, CKD and AKI patients and those with large variations in serum
protein levels should have their drug dosage individualized based on the
best available evidence
Drug dosing considerations for • The KDIGO AKI, AKIN, RIFLE, or pRIFLE criteria should be used to optimize
patients with AKI identification of high-risk patients
• High-risk medications and drugs with known nephrotoxic potential
should be identified proactively
• Vd of many medications is dramatically increased due to AKI and higher
loading doses are required to achieve optimal response and avoid
subtherapeutic levels
• Therapeutic drug monitoring is the gold standard and should be utilized
for those medications where serum drug concentrations can be obtained

Contd...
136 Section 1  Renal Replacement Therapy

Contd...

• Trends of serum creatinine and urine output should be assessed along


with volume status and should be utilized to guide drug dosing when
rapidly measurable indices are unavailable
• Patient-centered team approach should be practiced, in which a special
ICU pharmacist is included, so as to prevent medication-related problems
and improve medication use
Drug dosing considerations in • All medications should be given after dialysis (Dhd) to ensure active drug
patients on hemodialysis levels until next dosing
• A supplementary (Dsup) dose in addition to the dose adjusted to kidney
failure (Dfail) should be considered after dialysis to replace the fraction
removed by dialysis (Fr).
• Dhd = Dfail + Dsup, where Dsup = Fr (Dstart − Dfail)
• Dsup is derived from studies of low-flux nonsynthetic membranes;
therefore, it should empirically be increased by at least 50% when high-
flux synthetic dialyzers are used
• Extended dialysis regimens with high-diffusive membranes have been
associated with extensive drug clearances and Dsup should be increased
accordingly
Drug dosing in patients on • These recommendations should be used only as an initial guide in AKI
CRRT patients receiving CRRT
• For drugs like aminoglycosides and vancomycin the most effective
method for optimizing the dose is therapeutic drug monitoring
• When CRRT or EDD clearance data are available, the current literature
recommendations should be the logical starting dose for therapy.
Different treatment intensities for CRRT or EDD result in marked variability
in drug removal and thus, this literature may not be generalizable across
the multiple CRRT and EDD prescriptions that are used in practice
• Another method is to calculate the “total creatinine clearance” (CLcr) based
on the addition of the patient’s residual renal clearance and expected
extracorporeal clearance. This value can then be used to estimate a
maintenance dosing regimen based on medication dosing guidelines
specified for that resultant total CLcr range. Using this method, most drugs
will fall in the CLcr 25–50 mL/min range.
• A fourth method starts with the dose and dosing interval for a patient
with a GFR of 10 mL/min (anuric dose), and makes dosage adaptations
based on the drug fraction expected to be removed by extracorporeal
therapy (FrEC):
• Maintenance dose = Anuric dose/[1 − FrEC]
• Dosing interval = Anuric dosing interval × [1 − FrEC]
• A fifth method starts with a normal dose (Dn) and reduces dose based on
normal clearance (Clnorm), nonrenal clearance (Clnonrenal), effluent rate (Qeff ),
and sieving coefficient (SC)
• Dose = Dosen [Clnonrenal+(Qeff Χ SC)]/Clnorm
• CRRT and EDD education should be an integral part of critical care and
nephrology fellowship training programs.
(AKI: acute kidney injury; AKIN: Acute Kidney Injury Network; CKD: chronic kidney disease; CRRT: continuous
renal replacement therapy; EDD: extended daily dialysis; RIFLE: Risk, Injury, Failure, Loss, End-Stage; eGFR:
estimated glomerular filtration rate; CRRT: continuous renal replacement therapy; FDA: Food and Drug
Administration; pRIFLE: pediatric RIFLE; EMA: European Medicine Agency)
Chapter 17  Drug Dosing in Continuous Renal Replacement Therapy 137

KEY POINTS TO REMEMBER


■ In patients with renal function derangement, loading doses should be used in standard,
unmodified dosage as it reduces the time to attainment of steady state (helps in
achieving Cmax).
■ Since clearance is reduced as renal function deteriorates, maintenance doses should be
reduced or given at longer time intervals so as to reduce the risk of toxicity (it reduces the
trough levels Cmin).
■ Initiation of extracorporeal circuits, i.e. CRRT in patients with renal impairment adds to
the volume of distribution (Vd). Therefore, it is preferable to give antibiotics with large
therapeutic index like beta-lactams in aggressive dosing to compensate for increased Vd.
■ Patient’s renal function changes daily while they are connected to CRRT. Also, different
dose range should be chosen as per the site of infection, e.g. CNS, bone, endocardium,
etc. where tissue penetration is reduced. Therefore, antimicrobial dosing should be
individualized for every patient daily as per the patient’s changing needs. “One size fits all”
is not true in clinical practice.

SUMMARY
Drug dosing in CRRT is a complex phenomenon. Close monitoring of drugs, wherever possible,
should be done. Loading dose should never be compromised. Maintenance doses should be
changed either by increasing the duration especially in concentration-dependent antibiotics,
or by decreasing the dose but keeping the frequency of doses same in cases of time-dependent
antibiotic. The anuric maintenance dose has to be increased if filtration fraction exceeds 25%.
It is preferable to use single substances over combination therapies. One should be aware of
the risk of underdosing during effective CRRT. Antibiotics getting adsorbed in membrane like
fluoroquinolones, need higher dosing. Higher doses should also be considered if convective
therapies are used rather than diffusive therapies. Creatinine clearance is a good modality to
calculate dose but it ignores tubular drug handling. Therapeutic drug monitoring, if possible,
is the best option to decide on doses of drugs in CRRT (Tables 6 and 7).

Table 6: Antimicrobial drug doses in CVVH and CVVHD/CVVHDF.


Time dependent
Route of or concentration Drug dose Drug dose in
S. No. Drugs elimination dependent Drug dose CVVH CVVHD/CVVHDF IHD
1. Acyclovir Renal Time dependent 5–7.5 mg/kg 5–7.5 mg/kg 2.5 mg/kg
q 24 hr q 24 hr q 24 hr
Encephalitis/ Encephalitis/ Encephalitis/
Zoster-10 mg/kg Zoster-10 mg/kg Zoster 5 mg/
12 hr 12 hr kg q 24 hr
2. Ampicillin Renal Time dependent 3 g q 12 hr 3 g q 12 hr 1–2 g IV
q 12 hr
3. Aztreonam Renal Time dependent 1–2 g q 12 hr 2 g q 12 hr 1g q 24 hr
Contd...
138 Section 1  Renal Replacement Therapy

Contd...

Time dependent
Route of or concentration Drug dose Drug dose in
S. No. Drugs elimination dependent Drug dose CVVH CVVHD/CVVHDF IHD
4. Cefepime Renal Time dependent 1–2 g q 12 hr 2 g q 12 hr 2 g post-HD
5. Ceftriaxone Renal Time dependent 1–2 g q 12 hr 2 g q 12 hr 1–2 g q 12 hr
6. Ceftazidime Renal Time dependent 1–2 g q 12 hr 2 g q 12 hr 1 g then 1 g
post-HD
7. Ciprofloxacin Renal Concentration 200 mg q 12 hr 200–400 mg 400 mg
dependent q 12 hr q 24 hr
8. Colistin Renal Concentration 2.5 mg/kg 2.5 mg/kg 1.5 mg/kg
dependent q 48 hr q 48 hr q 24 hr
9. Polymyxin B Hepatic Concentration 15,000–25,000 15,000–25,000 No data
dependent U/kg/day q 12 hr U/kg/day q 12 hr
10. Fluconazole Renal Time dependent 200–400 mg 400–800 mg 400 mg then
q 24 hr q 24 hr 400 mg IV
q 24 hr
11. Imipenem Renal Time dependent 250 mg q 6 hr or 250 mg q 24 hr No data
500 mg q 8 hr
12. Levofloxacin Renal Concentration 250 mg q 24 hr 250 mg q 24 hr 500 mg then
dependent 250 mg
q 24 hr
13. Moxifloxacin Hepatic Concentration 400 mg q 24 hr 400 mg q 24 hr 400 mg
dependent q 24 hr
14. Piperacillin Renal Time dependent 2.25 g q 6 hr 2.25–3.375 g 2.25 g q 12 hr
q 6 hr
15. Vancomycin Renal Time dependent 1 g q 48 hr 1g q 24 hr 15–20 mg/kg
(CVVH: continuous venovenous hemofiltration; CVVHD: continuous venovenous hemodialysis; CVVHDF:
continuous venovenous hemodiafiltration; IHD: intermittent hemodialysis)

Table 7: Antimicrobial drug doses in SLED.


Route of Time dependent or
S. No. Drugs elimination concentration dependent Drug dose SLED
1. Meropenem Renal Time dependent 500–1,000 mg q 8 hr
2. Gentamicin Renal Concentration dependent Loading dose 6 mg/kg every 48 hours
followed by measurement of serum levels
for further dosing
3. Amikacin Renal Concentration dependent Loading dose 15–20 mg q 48 hr followed
by measurement of serum levels for further
dosing
4. Moxifloxacin Hepatic Concentration dependent No dose adjustment required

5. Colistin Renal Concentration dependent Loading dose of 6 mU followed by 9 mU in


3 divided doses in 24 hr
(SLED: sustained low efficiency dialysis)
Chapter 17  Drug Dosing in Continuous Renal Replacement Therapy 139

REFERENCES
1. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO
clinical practice guidelines for acute kidney injury. Kidney Int Suppl. 2012;2:1-138.
2. Ronco C, Ricci Z, De Backer D, et al. Renal replacement therapy in acute kidney injury: Controversy
and consensus. Crit Care. 2015;19:146.
3. Shaw AR, Chaijamorn W, Mueller BA. We under dose antibiotics in patients on CRRT. Semin Dial.
2016;29:278-80.
4. Beumier M, Casu GS, Hites M, et al. β-lactam antibiotic concentrations during continuous renal
replacement therapy. Crit Care. 2014;18(3):R105.
5. Ulldemolins M, Soy D, Llaurado-Serra M, et al. Meropenem population pharmacokinetics in
critically ill patients with septic shock and continuous renal replacement therapy: Influence of
residual diuresis on dose requirements. Antimicrob Agents Chemother. 2015;59(9):5520-8.
6. Kohama H, Ide T, Ikawa K, et al. Pharmacokinetics and outcome of tazobactam/piperacillin
in Japanese patients undergoing low-flow continuous renal replacement therapy: dosage
considerations. Clin Pharmacol. 2017;9:39-44.
7. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management
of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am
J Respir Crit Care Med. 2005;171(4):388-416.
8. Kashuba AD, Nafziger AN, Drusano GL, et al. Optimizing aminoglycoside therapy for nosocomial
pneumonia caused by gram-negative bacteria. Antimicrob Agents Chemother. 1999;43(3):623-9.
9. Trotman RL, Williamson JC, Shoemaker DM, et al. Antibiotic dosing in critically ill adult patients
receiving continuous renal replacement therapy. Clin Infect Dis. 2005;41(8):1159-66.
10. Sandri AM, Landersdorfer CB, Jacob J, et al. Pharmacokinetics of Polymyxin B in patients on
continuous venovenous haemodialysis. J Antimicrob Chemother. 2013;68(3):674-7.
11. Stanford Health Care Antimicrobial Dosing Reference Guide. [online] Available from: http://
med.stanford.edu/bugsanddrugs/dosing-protocols/_jcr_content/main/panel_builder/panel_0/
download/file.res/SHC%20ABX%20Dosing%20Guide.pdf. [Last accessed October, 2019].
12. Patel K, Roberts JA, Lipman J, et al. Population pharmacokinetics of fluconazole in critically ill
patients receiving continuous venovenous hemodiafiltration: Using Monte Carlo simulations
to predict doses for specified pharmacodynamic targets. Antimicrob Agents Chemother.
2011;55(12):5868-73.
13. González de Molina F, Martínez-Alberici Mde L, Ferrer R. Treatment with echinocandins during
continuous renal replacement therapy. Crit Care. 2014;18(2):218.
14. Bellmann R, Egger P, Gritsch W, et al. Amphotericin B lipid formulations in critically ill patients
on continuous veno-venous haemofiltration. J Antimicrob Chemother. 2003;51(3):671-81.
15. Heintz BH, Matzke GR, Dager WE. Antimicrobial dosing concepts and recommendations for
critically ill adult patients receiving continuous renal replacement therapy or intermittent
hemodialysis pharmacotherapy. 2009;29(5):562-77.
16. Manian FA, Stone WJ, Alford RH. Adverse antibiotic effects associated with renal insufficiency.
Rev Infect Dis. 1990;12(2):236-49.
17. Kimberly NB, Nicole TP, Troy JP, et al. Antibiotic dosing during sustained low-efficiency dialysis:
Special considerations in adult critically ill patients. Crit Care Med. 2011;39(3):560-70.
18. Eyler RF, Shvets K. Clinical pharmacology of antibiotics. Clin J Am Soc Nephrol. 2019;14(7):
1080-90.
19. Burkhardt O, Hafer C, Langhoff A, et al. Pharmacokinetics of ertapenem in critically ill patients with
acute renal failure undergoing extended daily dialysis. Nephrol Dial Transplant. 2009;24(1):267-71.
20. Sethi SK, Krishnappa V, Nangethu N, et al. Antibiotic dosing in sustained low-efficiency dialysis
in critically ill patients. Can J Kidney Health Dis. 2018;5:2054358118792229.
21. Li PK, Szeto CC, Piraino B, et al. ISPD peritonitis recommendations: 2016 update on prevention
and treatment. Perit Dial Int. 2016;36(5):481-508.
CHAPTER 18
Troubleshooting in Renal
Replacement Therapy
Kanwalpreet Sodhi, Niraj Tyagi, Diptimala Aggarwal, Sumati Verma

INTRODUCTION
Continuous renal replacement therapy (CRRT) remains a prevalent modality in critically ill pa­
tients. During CRRT, blood is pumped through the extracorporeal circuit. Although anticoagulants
such as heparin are commonly used, circuit clotting within the first 24 hours of therapy is a
common occurrence. This phenomenon is recognized as “artificial kidney failure” (AKF) and
the most common cause for AKF is circuit clotting. The interruption of the dialysis machine due
to any reason, for any period of time will adversely affect patient’s clinical management and
life of the dialysis circuit. Such circuit downtime contributes to inadequate therapy, avoidable
blood loss, increased cost, and typically wasted manpower dedicated to CRRT. If the operator
has an understanding of how the machine works and functions, dialysis runs more effectively.
Understanding how alarm systems work on CRRT machines is useful for troubleshooting,
whereby the bedside healthcare provider can quickly and accurately correct malfunctions.
In general, alarms used in biomedical equipment are classified according to severity of
problem and urgency for attention. The alarm colors on most of the dialysis machines remain
the same:
■ Green: All is running correctly.
■ Orange: A nonurgent alarm (e.g. bag change is due). During this alarm, the blood pump
heads will continue to turn and the machine functioning is unaffected.
■ Red: A serious problem. Blood pump heads will stop if this alarm is activated and the
machine will be practically nonfunctional at that time.
The various alarms on a dialysis machine include:
■ Access pressure alarms—low arterial pressure alarm/high venous pressure alarm
■ Filter pressure alarms—clotting vs clogging
■ Disconnection alarm
■ Air in the circuit alarm
■ Blood leak alarm.
Troubleshooting in a dialysis machine is an ongoing task. As 24 × 7 care providers in
intensive care unit (ICU), understanding the alarms and their cause is of utmost importance
Chapter 18  Troubleshooting in Renal Replacement Therapy 141

Fig. 1: Renal replacement therapy circuit showing various alarm sensors.

so as to correct them. Before understanding the alarms, we need to know about the pressure
monitorings in the renal replacement therapy (RRT) circuit (Fig. 1).

PRESSURE MONITORING
An extracorporeal circuit offers multiple resistance to blood flow and has several sensors,
which enable pressure monitoring at various levels of the circuit. When the CRRT machine
is primed and initiated to run, the baseline pressures are recorded by machine and deviation
from the baseline along with absolute value of pressure is used to sound alarms regarding
problems in circuit.

Measured Pressures
Inflow/Access Pressure
Access pressure is the negative pressure required to be generated to remove blood from the
patient. It is measured between the catheter and the blood pump. Since blood is actively
aspirated during dialysis, such pressures are typically negative, ranging between –50 mm Hg
and –200 mm Hg. Inflow pressure is an indicator of functioning of the vascular access. Acute
drops in inflow pressure may also be encountered during patient’s mobilization or coughing.

Outflow/Return Pressure
Return pressure is the positive pressure generated to return the blood to the patient. It is
measured between the filter and the patient on the return line and the pressures are positive,
142 Section 1  Renal Replacement Therapy

ranging from +50 mm Hg to +200 mm Hg. Outflow pressure is used for transmembrane pressure
(TMP) and pressure drop calculation.

Filter Pressure
Filter pressure is measured between the blood pump and the filter. It monitors the positive
pressure generated in the circuit immediately before the blood enters the hemofilter. It is the
highest pressure point in the circuit. It indicates the functional state of the hemofilter and
hollow­fiber permeability. A rising filter pressure may be indicative of filter clotting. Filter
pressure is also influenced by transmitted outflow pressures. In case outflow pressure is
elevated, the clotting of filter needs to be assessed based on the drop in filter pressure.

Effluent Pressure
Effluent pressure is measured in the effluent compartment, between the filter and the effluent
pump. It corresponds to the positive pressure required to generate the target ultrafiltration.
It can be negative also, depending on the mode of CRRT, like in continuous venovenous
hemofiltration (CVVH) mode, exchanges are generated by a negative effluent pressure. During
therapy, as membrane pores tend to undergo a “clogging” process, effluent pressures tend
to become more negative, which signifies the increased “effort” required by the system to
generate ultrafiltration.

Calculated Pressures
Filter Pressure Drop
Filter pressure drop represents the difference between outflow and filter pressures. Clogging
during CRRT worsens resistance to blood flow through filter and thus leads to increase in filter
pressure drop. A slow and continuous rise of pressure drop should be an alert to intervene,
aiming at minimizing clotting.

Transmembrane Pressure
The TMP is the pressure gradient on either side of the filter membrane. The hydrostatic and
oncotic pressure gradients across the filter determine the TMP and therefore it varies along
the length of the filter.
Transmembrane pressure can be estimated by the following formula:
TMP = [Filter Pressure + Return Pressure]/2 − Effluent Pressure
A rise in TMP can be secondary to membrane pores clogging or some form of clotting along
the circuit. Membrane clogging is associated with a slow but continuous rise in TMP with an
increasingly negative effluent pressure. Circuit clotting also leads to a rise in TMP, which might
be progressive but usually is a sudden event.
■ High TMP with normal return pressure suggests that clotting site is the dialysis filter.
■ High TMP with high return pressure suggests either the filter or the return line is having a
clot.
Chapter 18  Troubleshooting in Renal Replacement Therapy 143

ALARMS
Low-access Pressures Alarm
This is the alarm for venous side of the circuit.
Access pressure is the negative pressure created by the blood pump to draw blood out of
the patient and pushes into the machine. Low­access pressure alarm shows that pressure on
venous side of the circuit is extremely negative.
Normal range: Normally negative; −30 mm Hg to −150 mm Hg
Alarms, if <−250 mm Hg
(Important to remember: Pressure = flow × resistance)

Causes
■ Problems with vascular catheter: High resistance to flow between the patient and the blood
flow pump due to:
– Vascular catheter abutting against the vessel wall
– Vascular catheter lumen is obstructed due to clot
– Catheter lumen or vascular line is kinked, clamped, or misaligned
– Another catheter is aspirating blood from the same site
– Vascular catheter is of inappropriate size: narrow bore
– Vascular catheter is of poor design: a wide­bore catheter with a circular lumen should
have been inserted.
■ Problems with intravascular volume: poor blood flow due to:
– Hypovolemia
– Increased intrathoracic or intra­abdominal pressure, decreasing the venous flow past
the catheter tip
– Hyperventilating patient
■ Blood flow rate is set too high (Fig. 2).

Fig. 2: The CRRT machine interface showing low access pressure alarm.
144 Section 1  Renal Replacement Therapy

Troubleshooting
■ Check the circuit:
– Malpositioned catheter: Try to reposition the vascular catheter with a little external
manipulation to maintain alignment—rotate or pull out slightly.
– Obstructed vascular catheter due to clot: Clamp off lines and lumen, try to aspirate
lumen with 5 mL or 10 mL syringe to remove clot. If clot comes out with good access
restored, then flush with normal saline and reconnect line and undo the clamps. If clot
does not come out and you cannot withdraw any blood, you may need to cease the
treatment, return the blood, and get the vascular catheter resited.
– If vascular catheter or line is obstructed: Inspect the line; make sure all the lumens and
lines are straight and unclamped.
– Try reducing the blood pump speed down a little.
– If still not better, try swapping the access and return lumens (this will increase
recirculation).
– Press the blood pump and balance keys to recommence treatment.
■ Check the patient:
– Agitated patient plays havoc with the access pressure; encourage cooperation.
– Check for signs of decreased circulatory volume. Ensure there is enough venous blood.
– Ensure respiratory pattern is not responsible for the alarms.
(The nurse informs of a funny alarm that she has never seen: Access pressure: +20 mm Hg)

POSITIVE ACCESS PRESSURE IMPLIES ARTERIAL CANNULATION


High-return Pressure Alarm
This alarm is for arterial side of the circuit.
A positive pressure is generated by the return pump which sucks blood out of the filter and
pushes it into the patient. This alarm means that there is obstruction in return limb of circuit
or catheter.
Normal = 50–150 mm Hg; maximum pressure tolerated is around 300 mm Hg.
>300 mm Hg: “high­return pressure” alarm.

Causes
■ Vascular catheter lumen is clotted.
■ Lumen or line is kinked, clamped, or misaligned.
■ Dislodged or displaced vascular catheter and the return lumen is emptying into a
hematoma.
■ Arterial cannulation, which went unnoticed (Fig. 3).

Troubleshooting
■ Check the circuit:
– Check vascular catheter for kinks; make sure all the lumens and lines are straight and
unclamped.
Chapter 18  Troubleshooting in Renal Replacement Therapy 145

Fig. 3: The CRRT machine interface showing high access pressure alarm.

– Ensure the catheter is not dislodged; try to rotate the vascular catheter gently if possible;
might need to withdraw it slightly.
– Might need to temporarily stop the dialysis; aspirate the vascular catheter lumens and
try to suck out the clot, if any.
■ Check the patient:
– Ensure the vascular catheter is actually in a vein, and there is no hematoma around it
– May need to resite the vascular catheter
– Swapping lumens might help in this situation, worth a try.

Low-return Pressures Alarm


This alarm is for the arterial side of the circuit.
A “low­return pressure” alarm would usually only be triggered by a negative pressure
generated by return pressure gauge.
Lower limit for the alarm is ~0 mm Hg.

Causes
■ Low blood pump speed/low blood flow rate
■ Line disconnection—venous access line sucks the air
■ Postpump line is clamped just presensor, leading to 0 mm Hg pressure.

Troubleshooting
■ Check the circuit:
– Ensure no site of disconnection anywhere—starting from machine through venous side
of the circuit.
– Ensure no clamp anywhere in the circuit.
■ Check the patient:
– Make sure vascular catheter did not get pulled out by delirious patient
– Increase blood flow rate.
146 Section 1  Renal Replacement Therapy

High Filter Pressure (Filter Pressure Extremely Positive)


This is the alarm for the dialysis filter. Filter pressure gradually rises over the course of dialysis
session and this alarm usually indicates dying filter.
Normal difference between filter pressure and return pressure = 100–250 mm Hg.
Alarm usually occurs at >250 mm Hg.

Causes
■ Filter becomes clogged with filth
■ Natural filter degradation with dialysis course
■ Sudden rise may be due to kinking or clamping of the line
■ Clogging/embolus/clot in the return limb
■ Excessively high fluid replacement rate.
Important: Look for other high-pressure alarms
■ If return pressure is also high, it indicates a problem with the return limb
■ If only filter pressure is high, then problem is with the filter.

Troubleshooting
Check the circuit:
■ Ensure kink­free line going into the filter.
■ Ensure there is no clamp anywhere.
■ Ensure appropriate predilution replacement fluid flow rate.
■ If the filter has clotted, replace the filter.

Transmembrane Pressure Alarm


Transmembrane pressure is the positive pressure differential between blood and ultrafiltrate
(or effluent pressure). Few machines report the TMP together with, or instead of, the filter
pressure. TMP alarm usually indicates the dying filter. TMP tends to rise gradually over the
course of the dialysis session.
Normal < 250 mm Hg
Alarm occurs if TMP > 450 mm Hg
High TMPs with normal return pressures indicate a problem with the filter.

Causes
■ Clogged filter: Protein deposition in filter decreases membrane permeability
■ Sudden rise in TMP: Kinked or clamped filtrate line (from the filter to the effluent bag)
■ An embolus or clot in the filtrate line
■ Excessive ultrafiltration rate relative to blood flow rate
■ Replacement fluid rate too high for the filter size.

Troubleshooting
Check the circuit:
■ Check for clamp anywhere in the circuit
■ Flushing through the rescue line which may improve the function of the filter temporarily
Chapter 18  Troubleshooting in Renal Replacement Therapy 147
■ Increase the blood flow rate or decrease the dialysate flow rate
■ Increase predilution rate and decrease postdilution rate.

IDENTIFYING CLOGGING AND CLOTTING


Clogging
Regarding CRRT, the term “clogging” refers to slow but continuous deposition of proteins
and red cell debris in the dialysis filter membrane’s pores during therapy. Clogging leads to
decreased membrane permeability and decreased larger molecules’ sieving coefficients.
Major problems due to clogging are:
■ Blood loss/anemia
■ Increased cost: Filters are expensive
■ Decreases clearance rate due to interruptions.

Causes
■ High resistance to flow due to vascular catheter/line problem or hypovolemia
■ Inadequate anticoagulation
■ Excessive hemoconcentration in filter from high ultrafiltration rate relative to blood flow
rate (filtration fraction should not exceed 25% of the amount of plasma removed from
blood).
Over time, pores clogging may enhance dialysis filter fiber’s clotting. The process is
influenced by an interplay of blood rheology, dialysis blood inflow, membrane characteristics,
and site of replacement fluids.

Troubleshooting
■ Decrease replacement fluid rate
■ Shift over to continuous venovenous hemodialysis (CVVHD)
■ Citrate anticoagulation
■ Predilution.

Clotting
Clotting during CRRT refers to clotting of hollow fibers of dialysis filter, but can happen
anywhere in the dialysis circuit. Blood circulation through any extracorporeal circuit initiates
coagulation cascade through activation of platelets. Interaction of platelets, leukocytes and
various mediators lead to release of tissue factor, which in turn initiates thrombin generation,
resulting ultimately in fibrin formation. Fibrin along with activated platelets is deposited on
the dialyzer capillary (hollow fiber) surface and results in clot formation.
Clots are frequently observed at the venous bubble traps because the interface of air and
blood and turbulences in the bubble trap activate the coagulation cascade.
Clotting can be a slow and progressive process or can occur rapidly.

Causes
■ Slow blood flow rate
■ High ultrafiltration rate
148 Section 1  Renal Replacement Therapy

■ High hematocrit
■ Intradialytic blood product transfusion
■ Composition of the membrane
To summarize, clotting versus clogging:
■ Transmembrane pressure alarm occurs at >300 mm Hg.
■ “Filter clotting” alarm occurs if TMP or pressure drop increases 100 mm Hg above baseline.
■ Venous chamber clots increase outflow and transmitted filter pressures, whereas dialysis
filter clots increase only filter pressure. Both these lead to a secondary increase in TMP.
Clogging and clotting are associated with high filter pressure alarm. To differentiate between
clotting and clogging:
■ Increase in pressure drop (>150 mm Hg)—indicates clotting
■ Increase in TMP (>150 mm Hg)—indicates clogging.

Disconnection Alarm
This alarm indicates line separation or rarely disconnection from patient.
Alarm occurs if access pressure is more positive than −10 mm Hg and access pressure
operating point is more negative than −10 mm Hg.

Causes
■ Line disconnection
■ Kinked or clamped circuit before pressure sensor
■ Access pressure sensor not installed/failed/or debris in access sensor housing
■ Blood pump speed too slow relative to catheter performance.

Troubleshooting
■ Check circuit and patient; if no disconnection then override alarm circuit
■ Evaluate for circuit change
■ Declamp line clot excluding pressure sensor
■ Increase set blood flow rate.

Air Detection Alarm


It indicates air in the circuit or the bubble detector has found some small air bubbles in circuit
(often due to CO2 coming from hemofiltration bags).

Causes
■ Loose connections along the circuit
■ Improper priming of the circuit
■ Return line not installed correctly: Air is present down the return line at the air detector
■ Blood level is too low in bubble trap chamber
■ Air detector is detached from the return line.
Chapter 18  Troubleshooting in Renal Replacement Therapy 149

Troubleshooting
Check the circuit:
■ Look for any loose connections across the circuit
■ Make sure the air detector is properly attached
■ Ensure bubble trap is working properly
■ Look for actual bubbles and if possible, aspirate them
■ Follow instructions for degassing
■ If the circuit is full of froth, blood cannot be returned, you need to setup a new circuit.

Blood Leak Alarm


It indicates that the blood detector in the effluent line has found either blood or something, it
thinks is blood.

Causes
■ Ruptured filter membrane causing a leak of blood—ultrafiltrate is colored.
■ Severe hemolysis—free heme being picked up by the detector.
■ Recently dose of hydroxocobalamin which tends to discolor all body fluids—false positive
■ Dirty mirror in housing.

Troubleshooting
■ Stop dialysis immediately and replace filter
■ Clean the mirror in housing and replace the chamber
■ Consider false positives.
As plasma is present in the “ultrafiltrate”, the blood detection alarm will sound; so replace
the chamber in the circuit with the dummy chamber filled with water. Press the blood pump
and balance keys to recommence treatment.

Fluid Balance Alarm


Causes
■ Fluid bags moving below machine
■ Fluid bags not connected properly
■ Fluid bags need changing
■ Fluid lines are kinked or clamped.

Troubleshooting
■ Stop bags from moving
■ Check all the connections between the fluid bags and the lines—complete and tight
■ Ensure all the clamps are released and lines are not kinked
■ Change effluent and fluid replacement bags for fresh ones, ensuring to clamp off the lines
and the bags and unclamping once new bags are connected.
150 Section 1  Renal Replacement Therapy

INDICATIONS FOR CHANGING THE CIRCUIT AND FILTER


The main indications for ceasing treatments to change a filter and the circuit relate to the status
of the circuit and the vascular catheter access. These are measured by recording the different
pressures within the circuit. These are the main indications for ceasing treatment:
■ The prefilter pressure is consistently above 270 mm Hg
■ The TMP is consistently above 250 mm Hg
■ The filter is over 72 hours old
■ The patient’s blood results start showing poor clearance of solutes even when ongoing
CRRT, e.g. urea, creatinine, or potassium levels start to increase.
If you troubleshoot these indications with no improvement, it is better to return the
patient’s blood from the circuit before total occlusion occurs so as not to inadvertently lose
blood volume.

SUGGESTED READING
1. Bellomo R, Ronco C, Mehta R. Nomenclature for continuous renal replacement therapies. AJKD.
1996;5(Suppl 3):S2­7.
2. Claudio R, Bellomo R, Kellum J. Critical Care Nephrology, 2nd edition. Amsterdam, Netherlands:
Elsevier; 2008. pp. 1­1848.
3. Elliot D, Aitken L, Chaboyer W. ACCCN’s Critical Care Nursing, 2nd edition. Sydney: Elsevier
Mosby; 2007.
4. Gambro Renal Products. PRISMA System. An integrated system for continuous fluid management,
renal replacement therapies and therapeutic plasma exchange. Operator’s manual. [online]
Available from: https://www.crrtonline.com/docs/OperatorsPrismaEng.pdf. [Last accessed
October, 2019].
5. Zaccaria R, Baldwin I, Ronco C. Alarms and troubleshooting. Continuous Renal Replacement
Therapy. United Kingdom: Oxford University Press; 2009. p. 15.
CHAPTER 19
Peritoneal Dialysis in Intensive Care Unit
KS Nayak, SV Subhramanyam, Praveen K Etta, S Antony

CURRENT STATUS OF PERITONEAL DIALYSIS IN INTENSIVE CARE UNIT


Hemodialysis (HD) is considered as the “default therapy” for a patient presenting to the
intensive care unit (ICU) with uremic symptoms. This is due to the comfort level and
hence ease of initiating HD or other extracorporeal therapies in the ICU. Modalities
such as HD and continuous renal replacement therapy (CRRT) are related to significant
morbidities, which are associated with central venous catheter (CVC) usage leading to
bacteremia/septicemia and central venous stenosis. CVC is used for initial therapy in 80%
of HD initiations.1 HD with CVC is documented to cause more septicemia episodes, more
hospitalization, and increased mortality in the first 12 months as compared to peritoneal
dialysis (PD).2-8

ADVANTAGES AND DISADVANTAGES OF PERITONEAL DIALYSIS FOR


CRITICALLY ILL PATIENTS
Peritoneal dialysis patients have a more flexible lifestyle, more residual renal function,
and financial benefits compared to HD.9-13 In spite of the drawbacks, HD was practiced
more than PD by factors, which included promotion of HD by the industry.14 Studies
generally have shown urgent-start peritoneal dialysis (USPD) as a feasible modality
of renal replacement therapy (RRT) in the acutely presenting patient increasing PD as
the destination treatment for end-stage renal disease (ESRD).15-17 PD in the ICU started
immediately after Tenckhoff catheter insertion, is becoming more prevalent worldwide
as it can avoid expensive extracorporeal treatment modalities such as CRRT and online
hemodiafiltration.
Starting PD within 14 days of PD catheter insertion is defined as USPD. We feel USPD
does not completely reduce the need to intervene with urgent-start hemodialysis (USHD),
to treat certain serious urgent comorbidities in the first 48 hours. Such patients in our
152 Section 1  Renal Replacement Therapy

experience do well with emergent-start peritoneal dialysis (ESPD), whereby we start PD


immediately after catheter insertion, though up to 48 hours in stable patients is acceptable.
Such patients usually those with hyperkalemia, metabolic acidosis, pulmonary edema or
sepsis causing a hypercatabolic state, may need a couple of sessions of HD to stabilize
(Bimodal approach). Hypercatabolic patients frequently and the hemodynamically
unstable patients may need to continue CRRT. Situations such as combined uremic
and hyponatremic encephalopathic patients would ideally be suited for ESPD to avoid
central demyelinating syndromes. A dedicated and versatile surgeon is a boon for the
ESPD program, who would even insert the Tenckhoff catheter at bedside under local
anesthesia. Laparoscopic PD catheter insertion may not be feasible as that would entail
giving general anesthesia, which our patients may not tolerate. Song and her team as early
as two decades back, performed immediate-start, full-volume PD in ESRD patients using
manual exchanges with excellent results given the circumstances, and without using the
automated cycler, which we routinely use in our center, more so because of the labor-
intensive therapy that manual PD is.18
Most studies published have only have had patients being initiated on PD in the first 14 days
post catheter insertion.15-17 Avoiding CVC and HD completely in the ICU patients is possible
only when we initiate PD immediately on their presentation with an urgent insertion of PD
catheter insertion. An ESPD program is likely to increase PD as a long-term RRT modality in
the ESRD patients and also be the bulwark of a “PD First” program.

HOW TO INITIATE PERITONEAL DIALYSIS IN INTENSIVE CARE UNIT


Apart from the intensivists and the nephrologist, the bulwark of PD in the ICU has to be
a dedicated surgeon who is willing to extremely accommodate in inserting the catheter as
soon as the patient presents to the ICU and is willing to undergo emergent PD. The catheter
insertion is generally done under local anesthesia with a little sedation. The standard
Tenckhoff double cuff swan neck catheter is used and care is taken to ensure that the exit
site scalpel incision is kept minimum to reduce possibility of pericatheter leak subsequently.
Usually a short jab with the pointed end of the scalpel should suffice so that the catheter is
firmly ensconced in the exit site. Double suturing of the inner cuff deep to the rectus sheath
is done. Laparoscopic insertion is avoided as it needs general anesthesia (GA), which the
ICU patient generally do not tolerate. The other surgical steps will be the same. We generally
discourage the nephrologist performing the procedure as any oozing, accidental puncture of
blood vessels are handled promptly.
This modality should not be confused with the relatively outdated stylet-based acute non-
Tenckhoff catheters, which are not for long-term usage.
Chapter 19  Peritoneal Dialysis in Intensive Care Unit 153

DWELL VOLUMES OF PERITONEAL DIALYSIS FLUID


The nephrology staff must determine the dwell volume and number of exchanges to be
delivered during the automated peritoneal dialysis (APD) session. Patients with a smaller body
surface area (BSA) of 1.65 m2 or less can be initiated on dwell volumes of 500 mL. Dwell volume
can be increased to 750 mL in larger patients with a BSA of 1.65–1.8 m2, and a 1-L dwell volume
can be used in patients with a BSA exceeding 1.8 m2.
The number of cycler exchanges can be determined on the basis of clinical judgment of
uremic symptoms and assessment of underlying residual kidney function.

MAINTAINING THE PATIENT ON PERITONEAL DIALYSIS IN


INTENSIVE CARE UNIT
The preferred modality would be, to use the automated cycler, which is very easy to operate,
and is easily managed by the PD clinical coordinator and subsequently the ICU nurses.
PD fluid used is the standard bags, with those needing fluid removal using higher dextrose
concentration.

COMPLICATIONS
Complications were minimal with a slight increase in pericatheteric leak, which can
be managed by peritoneal rest. PD catheter blockage is also manageable by soap and
water enema administration, as they are usually due to catheter malposition, which gets
rectified by catheter repositioning that occurs with the bowel peristalsis occurring with
enemas.

CONCLUSION
We, in our Renal Intensive Care Unit (RICU) have been using ESPD as the preferred modality
for the acutely presenting patient with renal failure in the ICU, provided the patients have been
carefully selected and there is a good protocol and support in place.
This also obviates the need for CVC, which has a significant morbidity associated with it.
After recovery, patients can continue to perform APD/continuous ambulatory peritoneal
dialysis (CAPD) at home, in those who have ESRD.
This has enabled us to increase the uptake of PD as the preferred modality of treatment
for ESRD (Our own experience with ESPD in ICU has been depicted in Figure 1, and Tables 1
and 2).
154
Section 1  Renal Replacement Therapy

Fig. 1: Details of the study.


(PD: peritoneal dialysis)
Chapter 19  Peritoneal Dialysis in Intensive Care Unit 155

Table 1: Baseline characteristics.


ALL (n = 56) Conventional PD (n = 24) Emergent PD (n = 32)
Sex (M:F) 40 (71.4%):16 (28.6%) 20 (83.3%):04 (16.7%) 22 (64.7%):12 (35.3%)
Age (years) 55.5 ± 10.4 55.9 ± 10.6 55.3 ± 10.3
Comorbidities
DM 27 (48.2%) 08 (33.3%) 19 (59.4%)
HTN 49 (87.5%) 19 (79.2%) 30 (93.8%)
IHD 20 (35.7%) 09 (37.5%) 11 (34.4%)
PVD 08 (14.3%) 07 (29.2%) 01 (3.1%)
Diagnosis
ADPKD 01 (1.8%) 00 1 (3.1%)
CGN 12 (21.4%) 06 (25.0%) 06 (18.8%)
CIN 18 (32.1%) 09 (37.5%) 09 (28.1%)
DN 25 (44.6%) 09 (37.5%) 16 (50.0%)
#Group comparisons were performed by independent t-test
‡Group comparisons were performed by chi-squared test, Fisher’s exact test
(M:F- male:female; DM: diabetes mellitus; HTN: hypertension; IHD: ischemic heart disease; PVD: peripheral
vascular disease; ADPKD: autosomal dominant polycystic kidney disease; CGN: chronic glomerulonephritis;
CIN: chronic interstitial nephritis; DN: diabetic nephropathy; PD: peritoneal dialysis)

Table 2: Complications.
ALL (n = 56) Conventional PD (n = 24) Emergent PD (n = 32) P value‡
Exit site leak 03 (5.4%) 00 03 (9.4%) 0.123
Block at start 00 00 00 –
Block due to catheter migration 12 (21.4%) 04 (16.7%) 08 (25.0%) 0.452
Block cleared by enema (n = 12) 07 (58.3%) 04 (100%)|(n = 4) 03 (37.5%)|(n = 8) 0.038
Catheter repositioned (n = 05) 03 (60.0%) 00 03 (60.0%)|(n = 5) –
Peritonitis 03 (5.4%) 00 03 (9.4%) 0.123
Technique survival at 90 days 52 (92.9%) 23 (95.8%) 29 (90.6%) 0.454
‡Group comparisons were performed by chi-squared test and Fisher’s exact test.
(PD: peritoneal dialysis)

REFERENCES
1. Collins AJ, Foley RN, Herzog C, et al. US renal data system 2012 annual data report. Am J Kidney
Dis. 2013;61(1 Suppl 1):A7,e1-476.
2. Xue H, Ix JH, Wang W, et al. Hemodialysis access usage patterns in the incident dialysis year and
associated catheter-related complications. Am J Kidney Dis. 2013;61(1):123-30.
3. Perl J, Wald R, McFarlane P, et al. Hemodialysis vascular access modifies the association between
dialysis modality and survival. J Am Soc Nephrol. 2011;22(6):1113-21.
4. Oliver MJ, Verrelli M, Zacharias JM, et al. Choosing peritoneal dialysis reduces the risk of invasive
interventions. Nephrol Dial Transplant. 2012;27(2):810-6.
156 Section 1  Renal Replacement Therapy

5. Astor BC, Eustace JA, Powe NR, et al.; CHOICE Study. Type of vascular access and survival among
incident hemodialysis patients: the choices for healthy outcomes in caring for ESRD (CHOICE)
study. J Am Soc Nephrol. 2005;16(5):1449-55.
6. Johnson DW, Dent H, Hawley CM, et al. Associations of dialysis modality and infectious mortality
in incident dialysis patients in Australia and New Zealand. Am J Kidney Dis. 2009;53(2):290-7.
7. Ishani A, Collins AJ, Herzog CA, et al. Septicemia, access and cardiovascular disease in dialysis
patients: the USRDS wave 2 Study. Kidney Int. 2005;68(1):311-8.
8. Patel PR, Kallen AJ, Arduino MJ. Epidemiology, surveillance, and prevention of bloodstream
infections in hemodialysis patients. Am J Kidney Dis. 2010;56(3):566-77.
9. Koch M, Kohnle M, Trapp R, et al. Comparable outcome of acute unplanned peritoneal dialysis
and haemodialysis. Nephrol Dial Transplant. 2012;27(1):375-80.
10. Tam P. Peritoneal dialysis and preservation of residual renal function. Perit Dial Int. 2009;29(Suppl
2):S108-10.
11. Moist LM, Port FK, Orzol SM, et al. Predictors of loss of residual renal function among new dialysis
patients. J Am Soc Nephrol. 2000;11(3):556-64.
12. Blagg CR. Dialysis composite rate bundling: potential effects on the utilization of home hemodialysis,
daily and nocturnal hemodialysis, and peritoneal dialysis. Semin Dial. 2011;24(6):674-7.
13. Klarenbach S, Manns B. Economic evaluation of dialysis therapies. Semin Nephrol. 2009;29(5):
524-32.
14. Golper TA, Saxena AB, Piraino B, et al. Systematic barriers to the effective delivery of home dialysis
in the United States: a report from the Public Policy/Advocacy Committee of the North American
Chapter of the International Society for Peritoneal Dialysis. Am J Kidney Dis. 2011;58(6):879-85.
15. See EJ, Cho Y, Hawley CM, et al. Early and late patient outcomes in urgent-start peritoneal dialysis.
Perit Dial Int. 2017;37(4):414-9.
16. Masseur A, Guest S, Kumar V. Early technique success after initiation of treatment with urgent-start
peritoneal dialysis. Adv Perit Dial. 2014;30:36-9.
17. Arramreddy R, Zheng S, Saxena AB, et al. Urgent-start peritoneal dialysis: a chance for a new
beginning. Am J Kidney Dis. 2014;63(3):390-5.
18. Song JH, Kim GA, Lee SW, et al. Clinical outcomes of immediate full-volume exchange one year
after peritoneal catheter implantation for CAPD. Perit Dial Int. 2000;20(2):194-9.
CHAPTER 20
Hemoperfusion for the
Treatment of Poisoning
Ganshyam Jagathkar, Nandhakishore Jampala, Chandreshkumar Sudani

INTRODUCTION
Hemoperfusion (HP) is an extracorporeal method of eliminating a toxin, in which blood passes
through a cartridge (containing either activated charcoal or ion-exchange resin) incorporated
into the dialysis circuit.1,2 It is based on the principle of “adsorption” where the concentration
of a substance/toxin is decreased by perfusing the blood through a specialized column/
cartridge, thereby decreasing its toxicity.1,3
It was first successfully used in patients with overdosage/poisonings early in the 1970s
and was even the preferred method over hemodialysis till the recent times due to the superior
clearance rates.1 But with the advent of advanced and efficient dialytic modalities (high-flux,
high-efficiency dialysis filters), it is now being used less frequently across the world.4 Despite
its efficacy to remove the specific toxins that are even tightly bound to the proteins, it is now
not performed routinely due to the higher rates of complications associated with it and due to
the significantly higher costs of the cartridges (Box 1).
In this chapter, we will discuss about the technical considerations of HP, the various
factors influencing the clearance of toxins through HP, the components of the circuit used for
HP, the properties and types of adsorbents used in HP, various complications of HP, current
applications, and future research.

CONSIDERATION OF HEMOPERFUSION IN A POISONED PATIENT


Majority of poisoned patients presenting to the hospital recover well most of the times with the
general standard supportive care. HP is reserved for only small subsets of patients who have
Box 1: Toxins amenable for hemoperfusion.3,5
• Lipophilic drugs
• Barbiturates
• Nonbarbiturate hypnotics and sedatives
• Tranquillizers and anticonvulsants
• Digitalis compounds
• Paraquat and other herbicides
• Aminophylline and theophylline
• Methanol and ethylene glycol
158 Section 1  Renal Replacement Therapy

Box 2: Clinical criteria for considering extracorporeal therapy/hemoperfusion.3,5


• Poison likely to cause serious deterioration despite standard measures
• Impairment of body’s endogenous clearance mechanisms (hepatic and renal insufficiency)
• Signs and symptoms of severe intoxication like hypoventilation, hypothermia, and CNS depression (coma)
• Toxins leading to severe hemodynamic instability with severe metabolic derangements
• If the poison’s extraction ratio is more than the body’s endogenous clearance rate
(CNS: central nervous system)

life-threatening toxicity, who have high likelihood of permanent disability or develop toxicity
despite standard supportive measures, provided the toxin is cleared through extracorporeal
method (Box 2).6

DETERMINANTS OF TOXIN REMOVAL BY HEMOPERFUSION


The physicochemical and pharmacokinetic properties of a toxin determine whether it can be
eliminated through an extracorporeal technique or not.3
■ Molecular weight (MW): In general, substances with a lower molecular weight have a
better chance of removal through extracorporeal techniques.6 However, it does not have a
major influence on clearance by HP. As even very large proteins are adsorbed on to the HP
column, as such there is no absolute cutoff value of molecular weight for a substance.1,4,7
■ Volume of distribution (Vd): It is the most important factor influencing the effective
removal of a toxin by HP.6 Toxins with larger Vd get distributed more into the extravascular
tissues, hence may not be amenable for removal. Poisons with smaller Vd (<1 L/kg) can be
removed more easily.8
■ Hydrophilicity/Lipophilicity: Water-soluble poisons (exhibit smaller Vd) are cleared by most
of the extracorporeal therapies. Lipophilic poisons (have large Vd) get readily distributed
to adipose tissues, making their clearance difficult.6,8 But with HP (especially with resin
columns), clearance of lipophilic compounds is favored.1
■ Protein and tissue binding: Poisons that are >80% protein bound are poorly removed by
HP. Since HP removes the unbound/free fraction, toxins with very high protein binding
have poor elimination with HP. Hence, it may not be advisable to use HP as a method of
elimination in compounds with high protein binding.1
■ Endogenous clearance: It is the patient’s intrinsic ability to clear a poison from the circulation
(with both renal and nonrenal clearance mechanisms). In conditions, where systemic
clearance is low [as in chronic kidney disease (CKD) patients], HP may increase the clearance
of a toxin to a significant extent. But with a good endogenous clearance (>4 mL/min/kg), the
efficacy of HP is doubtful (Flowchart 1).1,6

TECHNICAL CONSIDERATIONS
Components of Hemoperfusion Circuit
The extracorporeal circuit used for HP is similar to the one used for hemodialysis or
hemofiltration. It consists of an adsorbent, which is perfused by patient’s blood. A peristaltic
pump via the blood tubings circulates the blood through the adsorbent cartridge.
Chapter 20  Hemoperfusion for the Treatment of Poisoning 159
Flowchart 1: Overall clinical approach for considering hemoperfusion.

(CVVH: continuous venovenous hemofiltration; HD: hemodialysis; TPE: therapeutic plasma exchange)

Table 1: Commercial hemoperfusion adsorbents.1,3,9


Name of adsorbent Company Material
Adsorba 150/300c Gambro 150 or 300 g of charcoal coated with cellulose acetate
Amberlite XAD-4, XAD-7 Sigma-Aldrich XAD-4 is derived from polystyrene-divinyl benzene
XAD-7 from polyacrylic ester-divinylbenzene
Hemoresin Braun 350 g uncoated XAD-4 resin
Hemocol 100 Smith and Nephew 100 g coconut shell acrylic-hydrogel coated charcoal
packed in polystyrene casing
Alu-kart National medical care 100 g or 155 g of encapsulated colloid charcoal
ACAC Chang Albumin-collodion coated charcoal

■ Adsorbent: The structure and properties of the adsorbent (cartridge/column) are the key
determinants of the efficacy of HP.
An ideal adsorbent should have the following properties:4,9,10
■ High selectivity/affinity toward a toxin.
■ Should have high and rapid capacity of adsorption.
■ Should be chemically and thermally inert.
■ Should be mechanically strong to avoid damage (crushing, erosion and fouling).
■ Should have good biocompatibility.
■ Should have low solubility.
■ Should allow easy filling and free flow of blood with empting of its bed.

Types of Adsorbents
Two types of adsorbents are presently available in the clinical practice.
1. Natural adsorbents: (a) Zeolite (aluminum silicate)—is an inorganic polymer with high
porosity; (b) porous carbons—cellulose derived organic polymer; and (c) activated
charcoal.10,11
2. Synthetic adsorbents: Resins (polymerizable monomers built up into large molecules)
(Table 1).
160 Section 1  Renal Replacement Therapy

Adsorbents usually exist as granules, beads, spheres and fibers with a diameter of
50 μm–1.2 cm. Activated charcoal shows enhanced adsorption of hydrophilic compounds
whereas resins exhibit increased adsorption and clearance of lipophilic compounds.4,12

Biocompatibility of Adsorbents
■ The adsorbent should be mechanically strong to prevent its damage with crushing and
release of the particles into the systemic circulation. To prevent this, they are incorporated
with a screen, which allows free flow of blood but prevents the dissipation of fragments.10
■ The inner surface of the adsorbent must be compatible with blood to avoid cell clogging,
protein deposition, and other effects like complement activation.10,12 These effects can be
minimized by coating the surface with a biocompatible material like polysulfone.

Other Factors which Influence the Adsorptive Capacity


■ Mass: The larger the mass (density) of adsorbent on the column, the more is the toxin
clearance.1
■ Surface area: Higher the surface area, more the adsorption (e.g. Amberlite XAD-4 has more
surface area of 750 m²/g than the XAD-2 which has only 350 m²/g).1,4,9
■ Surface area to volume ratio (S/V): It is very high in adsorbent particles with high surface
area.10
■ Size and configuration of the pores: Macroporous adsorbents (>50 nm) have more capacity
of adsorption than microporous adsorbents (<20 nm).
■ Number of cartridges: Usually single cartridge is sufficient in treatment of most poisonings,
but two or more cartridges can be used in series to enhance the poison removal.
■ Duration of HP: Saturation of the HP cartridge occurs after 4–6 hours of continuous use, so
it is necessary to replace the cartridge frequently.
■ Blood flow: The rate of blood flow across the HP cartridge influences the clearance rates of
poison. This is more often seen with poisons that are less protein bound. But usually the
blood flow rates are limited to around 300–350 mL/min to minimize other complications
like hemolysis.1
Utilization of adsorbents: The sorbents can be applied in different modalities.9,10
■ Hemoperfusion—in which there is direct contact of blood with the adsorbent.
■ Hemoperfusion–hemodialysis (HPHD)—in which the adsorbent is placed in series before
the dialyzer.
■ Paired filtration dialysis (PFD)—in which the adsorbent is placed in-line with the
ultrafiltrate obtained from the hemofilter.
■ Coupled plasma filtration adsorption (CPFA)—in which the adsorbent is placed in-line
with the plasma filtrate produced from a plasma filter (Table 2).

Adverse Effects of Hemoperfusion


Most of the complications occur secondary to the nonspecific adsorption of other normal
biological components.12–14
■ Thrombocytopenia and leucopenia
■ Hypocalcemia, hypophosphatemia, hypoglycemia
Chapter 20  Hemoperfusion for the Treatment of Poisoning 161

Table 2: Modes of sorbent application.10


1. HP

2. HPHD

3. PFD

4. CPFA

(CPFA: coupled plasma filtration adsorption; HP: hemoperfusion; HPHD: hemoperfusion–hemodialysis;


PFD: paired filtration dialysis)

■ Hypotension
■ Coagulopathy (decreased Fibrinogen)
■ Complement activation [systemic inflammatory response syndrome (SIRS) response]
■ Chemoembolization and pyrogenic reactions.

RECOMMENDATIONS
■ On the basis of current data available we believe that the role of HP in the treatment of
poisonings is limited.
■ No recommendation for or against can be made on the role of HP in the treatment of
poisonings.

SUMMARY
■ Conventional extracorporeal therapies like HD/HF (using principle of diffusion and
convection) are ineffective in removing protein bound, lipophilic substances with high
volume of distribution. Hence, HP still remains a valid alternative in removing such poisons
from the circulation.
162 Section 1  Renal Replacement Therapy

■ In spite of its strong physiological basis and effective clearance of toxins from the circulation,
the use of HP has been declining in recent years, due to its side effects, cost constraints, and
advances in other techniques.2
■ The type of adsorbent and the utilization of adsorbent in different modes need to be
considered carefully while starting HP.
■ There are no major RCTs done comparing the efficacy of HP versus other modalities of
extracorporeal therapies. So far, there is only large number of case reports and observational
studies done on the role of HP in poisonings.
■ Recently, a multinational consortium known as the EXTRIP workgroup (Extracorporeal
Treatment in Poisoning) aimed to clarify the role of extracorporeal therapies in clinical
practice, but their recommendations are not definitive due to low quality of available
data.15,16

REFERENCES
1. Ghannoum M, Bouchard J, Nolin TD, et al. Hemoperfusion for the treatment of Poisoning:
technology, determinants of poison clearance, and application in clinical practice. Semin Dial.
2014;27(4):350-61.
2. Shalkham AS, Kirrane BM, Hoffman RS, et al. The availability and use of charcoal hemoperfusion
in the treatment of poisoned patients. Am J Kidney Dis. 2006;48(2):239-41.
3. Winchester JF. Dialysis and hemoperfusion in poisoning. Adv Ren Replace Ther. 2002;9(1):26-30.
4. Bouchard J, Roberts DM, Roy L, et al. Principles and operational parameters to optimize poison
removal with extracorporeal treatments. Semin Dial. 2014;27(4):371-80.
5. Wichester JF, Harbord NB. Intoxications amenable to extracorporeal removal. Adv Chronic Kidney
Dis. 2011;18(3):167-71.
6. Ghannoum M, Hoffman RS, Gosselin S, et al. Use of extracorporeal treatments in the management
of poisonings. Kidney Int. 2018;94(4):682-8.
7. Wolley M, Jardine M, Hutchison CA. Exploring the clinical relevance of providing increased
removal of large middle molecules. Clin J Am Soc Nephrol. 2018;13(5):805-14.
8. Roberts DM, Buckley NA. Pharmacokinetic considerations in clinical toxicology: clinical
applications. Clin Pharmacokinet. 2007;46(11):897-939.
9. Ronco C, Bordoni V, Levin NW. Adsorbents: From basic structure to clinical application. Contrib
Nephrol. 2002;(137):158-64.
10. Ronco C, Clark WR, Ferrari F. Extracorporeal blood purification techniques beyond dialysis
(Section 27), Sorbents: From basic structure to Clinical application (chapter 189). In: Ronco C,
Bellomo R, Ricci Z (Eds). Critical Care Nephrology, 3rd edition. USA: Elsevier; 2019.
11. Winchester JF, Ronco C, Brady JA, et al. Sorbent augmented dialysis: minor addition or major
advance in therapy? Blood Purif. 2001;19(2):255-9.
12. Gil HW, Kim SJ, Yang JO, et al. Clinical outcome of hemoperfusion in poisoned patients. Blood
Purif. 2010;30(2):84-8.
13. Haapanen EJ. Hemoperfusion in acute intoxication. Clinical experience with 48 cases. Acta Med
Scand Suppl. 1982;668:76-81.
14. Hennemann H, Richter IE, Brunswig D, et al. Hamoperfusion-pro und kontra. Klin Wochenschr.
1977;55:53-7.
15. Lavergne V, Nolin TD, Hoffman RS, et al. The EXTRIP (EXtracorporeal TReatments In Poisoning)
workgroup: guideline methodology. Clin Toxicol (Phila). 2012;50(5):403-13.
16. The Extracorporeal Treatments in Poisoning Workgroup. [online] Available from: http://www.
extrip-orkgroup.org. [Last accessed October, 2019].
CHAPTER 21
Therapeutic Apheresis
Vaishali Solao

INTRODUCTION
Therapeutic apheresis is a well-established treatment commonly used in intensive care for
various disorders. It is essential for an intensivist to be familiar with all aspects of the procedure.
This chapter aims at an overview of therapeutic apheresis with particular focus on technical
aspects, which are seldom described in detail.

TERMINOLOGY AND DEFINITIONS


Apheresis is derived from the Greek word aphaíresis, which means to separate. When used
in the context of blood and its components, it implies removal of one of its components, i.e.
red blood cells (RBCs ), plasma, leukocytes, immunoglobulin G (IgG), immune complexes or
any other harmful agents responsible for disease manifestations. When used for the purpose
of blood and component donation, it is called apheresis. When used for removal of harmful
agents in an exchange, it is defined as therapeutic apheresis.
Table 1 explains the various terminologies used.1 Plasma exchange and plasmapheresis
are technically different procedures but the terminology is often used interchangeably leading
to confusion. Table 1 gives definitions and all the terminologies in context of therapeutic
apheresis. The list is expansive; only the relevant procedures for critical care are explained.
To discuss the details of each of these and dissect the strength of evidence in various diseases
is beyond the scope of this chapter. For the need of brevity, we will discuss the most common
clinical conditions requiring apheresis in the intensive care setting followed by description of
the technical aspects of the procedure.
Of all the apheresis procedures mentioned in Table 1, plasma exchange and RBC exchange
are two procedures of particular interest to critical care specialists.

THERAPEUTIC PLASMA EXCHANGE


Therapeutic plasma exchange (TPE) and plasmapheresis are not interchangeable
terminologies. This chapter will use TPE so as to avoid confusion. Plasma exchange involves
removal of large volumes of plasma, 1–1.5 times the patient’s own plasma volume, with
164 Section 1  Renal Replacement Therapy

Table 1: Terminologies.
Terminology Definition
Apheresis A process in which blood of the patient or donor is separated into one or more
components for removal and the rest is recirculated back with or without
replacement fluid
Plasmapheresis A process by which plasma is separated and collected for use and rest is reinfused
without replacement fluid. Used to collect plasma for blood components or plasma
derivative
DFPP (Double filtration A variation of plasmapheresis where a second filter selects out the molecule
plasmapheresis) of interest and discards and rest of plasma is reinfused with no or minimal
replacement
TPE (Therapeutic A process by which plasma is separated from the cellular components and is
plasma exchange) discarded, equivalent amount of replacement fluid is replaced
HVPE (High-volume 15% of body weight, i.e. 8–10 L of plasma is exchanged at rate of 1–2 L per hour and
plasma exchange) replaced with equal volume of plasma
Leukocytapheresis A process by which the WBC are separated from the blood and remainder is
reinfused without replacement fluids
Thrombocytapheresis Platelets are separated and removed and rest reinfused
RBC exchange Patient’s RBC are separated and removed and infused with new RBC plus crystalloid
or colloid solution
Immune adsorption A process by which specific immunoglobulins are removed by binding them to an
active component on the device
(RBC: red blood cell; WBC: white blood cell)

simultaneous replacement of volume by using either plasma or crystalloids and colloids.


Patient’s own expected plasma volume (EPV) is calculated as follows:1
EPV = BW × 1/13 × (1 − Ht/100)
[BW: Body weight (kg); Ht: Hematocrit (%)]
Plasma exchange works by removing the antibodies, immune complexes, or cytokines
responsible for the illness. It is possible that the effect extends beyond this narrow zone to
immunomodulation also thereby explaining its benefit for extended periods of time. The
techniques used for the exchange are basically two—first by using filters of a particular size
to separate the plasma from the cellular components, and the second is by using density
to separate the two, which is done by centrifugation. Choice between the two methods,
membrane filter-based and centrifugation-based technologies, in India is largely dependent
on resource and expertise availability in respective institutions. Centrifugation-based apheresis
machines are fully automated with total control on exchanged volume and online monitoring
and replacement of calcium to neutralize citrate. Filtration membrane-based TPE is widely
practiced in India due to wider availability of machines. It involves manual removal of plasma
using a plasma filter (Plasmaflo) and blood pump of a dialysis machine.
Usually removal of 1–1.5 times of plasma volume will lead to removal of 60–70% of the
initial concentration of the culprit substance in plasma. Higher volume exchanges however,
do not have incremental benefit due to dilution effect of replacement fluid. Plasma exchange
Chapter 21  Therapeutic Apheresis 165
removes plasma in bulk and hence is nonselective. Besides removing the substance of interest,
it removes other components like coagulation factors, antibiotics, enzymes, immunoglobulins,
etc., which could be a source of potential adverse effects. Despite removal of coagulation
factors, most of these are replenished in the body in 24–48 hours hence, replacement fluid can
be albumin and not plasma always as long as there is no liver failure.
Double filtration plasmapheresis (DFPP) is a variation of plasmapheresis. After separation
of plasma, using plasma filter (Plasmaflo) the substance of interest is further removed
using a second filter (Cascadeflo EC, Evaflux 2A); patient’s own plasma is returned back to
the circulation. Advantages are a closed loop, decreased risk of infections, and minimal
replacement fluid. In essence, it is not an exchange.
Choice of replacement fluid is subject to etiology of underlying diseases. For example,
in acute liver failure (ALF) and thrombotic thrombocytopenic purpura (TTP), almost all the
volume is replaced with plasma. On the other hand, for immunological indications such as
myasthenia gravis, Wegener’s granulomatosis replacement fluid could be a combination
of crystalloids and albumin (4–5% albumin or 20% albumin and saline). In Wegener’s
granulomatosis, when diffuse alveolar hemorrhage is an indication, then plasma is the
preferred replacement fluid as these patients will worsen due to the postprocedure dilutional
coagulopathy if plasma not used.2
Number of sessions and the frequency of sessions vary from disease to disease and the
response to TPE. In ALF three sessions of high-volume exchanges are recommended while in
TTP first three sessions daily followed by tapering until response is usually recommended.3
For myasthenia gravis five sessions daily or every other day are recommended as primary
treatment of crisis and prethymectomy. For acute Guillain–Barré syndrome (GBS), intravenous
immunoglobulin G (IVIgG) is treatment of choice but in resource-restricted situations, plasma
exchange is equally effective and a cheaper alternative. TPE can also be used in event of
failure of response to IVIgG in myasthenic crisis or GBS keeping in mind that the IVIgG will
be removed by plasma exchange; it is a grade 3 recommendation. ABO-incompatible solid
organ transplant is another area where TPE has been exploited to reduce antibody titers to a
predetermined level. In this situation, DFPP may have a unique role and distinct advantages.4
Table 2 gives a summary of diseases that have a grade 1 recommendation for TPE. Grade 1
includes all disorders for which apheresis is first line of therapy either alone or in combination
with other modes of treatment.
Anticoagulation: Citrate is an almost universally used anticoagulant for plasma exchange via
the centrifugation technique; heparin can be used for membrane-based techniques.
Adverse effects reported in literature vary in incidence from 4% to 30%. Most are minor
reactions related to transfusions of products, including allergic reactions but more severe
complications like transfusion-related acute lung injury (TRALI) and infections due to exposure
to large amounts of plasma are also possible. Thrombocytopenia and hypofibrinogenemia
are also known immediately after TPE. Vascular access-related complications are inherent
to the procedure. Hypocalcemia also may require attention and correction post-procedure.
Antibiotics are also removed by TPE, however, currently no data is available on various
antibiotics and their percentage of excretion. High-volume plasma (HVP) is more likely to lead
to the lowering of therapeutic levels.
166 Section 1  Renal Replacement Therapy

Table 2: Diseases with grade 1 recommendation for TPE.


Disease name Indication Apheresis
AIDP Primary treatment TPE
ALF HVPE
ANCA associated RPGN DAH, AKI dialysis dependence TPE
Goodpasture’s syndrome DAH AKI no dialysis TPE
CIDP TPE
Familial hypercholesterolemia Pancreatitis TPE/LDL apheresis
Hyperviscosity in monoclonal Symptomatic, prophylaxis for Rituximab TPE
gammopathies
ABO-incompatible liver transplant Desensitization TPE/IA/DFPP

Myasthenia gravis Crisis, prethymectomy TPE


ABO-incompatible renal transplant Desensitization LD TPE/IA/DFPP

Sickle cell disease Acute stroke, stroke prophylaxis. Iron RBC exchange
overload
Malaria Parasitic index >10% RBC exchange
TMA drug associated Ticlopidine associated TPE
TTP Primary treatment TPE
Wilsons disease Fulminant TPE
(AIDP: acute inflammatory demyelinating polyneuropathy; AKI: acute kidney injury; ALF: acute liver failure;
ANCA: antineutrophil cytoplasmic antibodies; CIDP: chronic inflammatory demyelinating polyneuropathy;
DAH: diffuse alveolar hemorrhage; DFPP: double filtration plasmapheresis; HVPE: high volume plasma
exchange; IA: immune absorption; LDL: low-density lipoprotein; RBC: red blood cell; RPGN: rapidly progressive
glomerulonephritis; TMA: thrombotic microangiopathy; TPE: therapeutic plasma exchange; TTP: thrombotic
thrombocytopenic purpura)

RED BLOOD CELL EXCHANGE


Exchange transfusion is rarely used in the intensive care units. Two indications, where it
remains a standard of care, are falciparum malaria with high parasite index and sickle cell
disease with hemolytic crisis. Exchange can be done by manual or automated means. RBC
exchange offers an effective and rapid way of clearing HbS RBCs. Volume of exchange depends
on the target HbS to be achieved, usually <30%, and target hematocrit (Hct) to be achieved,
usually 33%. One procedure usually suffices to treat acute chest syndrome or for prevention of
stroke. For falciparum malaria indication is for high parasitic index (>10%). RBC exchange or
manual exchange transfusion (exchange transfusion; with whole blood or RBC replacement)
in severely ill patients with hyperparasitemia (>10%) appears to improve blood rheological
properties, capillary perfusion, and microcirculatory flow by removing infected RBCs thus
reducing parasite load and modulating cytoadherence.5 As per the American Society for
Apheresis (ASFA) guidelines, this is a grade 3 recommendation, no randomized clinical trials
(RCTs) have been published so far.
Chapter 21  Therapeutic Apheresis 167

Abbreviations
AIDP Acute Inflammatory Demyelinating Polyneropathy
AKI Acute Kidney Injury
ALF Acute Liver Failure
ANCA Antineutrophil Cytoplasmic Antibodies
CIDP Chronic Inflammatory Demyelinating Polyneropathy
DAH Diffuse Alveolar Hemorrhage
DFPP Double Filtration Plasmapheresis
GBS Guillain-Barré Syndrome
HVPE High Volume Plasma Exchange
IA Immune Absorption
IgG Immunoglobulin G
IVIgG Intravenous Immunoglobulin G
LDL Low density Lipoprotein
RBC Red Blood Cell
RPGN Rapidly Progressive Glomerulonephritis
TMA Thrombotic Microangiopathy
TPE Therapeutic Plasma Exchange
TRALI Transfusion-related Acute Lung Injury
TTP Thrombotic Thrombocytopenic Purpura

SUMMARY
Plasma exchange is an established modality of treatment of various disorders seen in critical
care. It is a safe procedure and majority of the side effects are minor and manageable. The ASFA
in 2016 published a detailed special issue on guidelines for therapeutic apheresis in clinical
practice.6 It is recommended to refer to the guidelines for details of various clinical entities
and the level of recommendations as of today. DFPP and immune adsorption are variants of
plasmapheresis that find application in various circumstances, such as ABO-incompatible
solid organ transplant, but are costlier than simple TPE.

REFERENCES
1. Winters JL. Plasma exchange: concepts, mechanisms, and an overview of the American Society
for Apheresis guidelines. Hematology Am Soc Hematol Educ Program. 2012;2012:7-12.
2. Klemmer PJ, Chalermskulrat W, Reif MS, et al. Plasmapheresis therapy for diffuse alveolar
hemorrhage in patients with small-vessel vasculitis. Am J Kidney Dis. 2003;42(6):1149-53.
3. Larsen FS, Schmidt LE, Bernsmeier C, et al. High-volume plasma exchange in patients with acute
liver failure: An open randomised controlled trial. J Hepatol. 2016; 64(1):69-78.
4. Jha PK, Tiwari AK, Bansal SB, et al. Cascade plasmapheresis as preconditioning regimen for ABO-
incompatible renal transplantation: a single-center experience. Transfusion. 2016;56(4):956-61.
5. Riddle MS, Jackson JL, Sanders JW, et al. Exchange transfusion as an adjunct therapy in severe
Plasmodium falciparum malaria: a meta-analysis. Clin Infect Dis. 2002;34(9):1192-8.
6. Schwartz J, Padmanabhan A, Aqui N, et al. Guidelines on the Use of Therapeutic Apheresis in
Clinical Practice-Evidence-Based Approach from the Writing Committee of the American Society
for Apheresis: The Seventh Special Issue. J Clin Apher. 2016;31(3):149-62.
CHAPTER 22
Extracorporeal Therapies in Sepsis
Yash Javeri, Ravi Jain, Sandesh KJ

INTRODUCTION
Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to
infection. Sepsis and septic shock represents most dramatic consequence of infection.1 Despite
better understanding of pathobiology of sepsis and improved care process, mortality remains
high. This fosters a continuous search for novel therapies going beyond objective correction
of oxygenation, hemodynamic and other objective clinical end points. Research continues
investigating the modulation of the inflammatory response for limiting the harmful action of
the bacterial products. Response to sepsis and to modalities to treat it also shows variations in
genomic groups. Immunological dysfunction is pivotal in pathogenesis of sepsis, and treatment
modalities need to address this dysfunction (Flowchart 1). Trident approach in sepsis suggests
antimicrobials, immunomodulation, and multiorgan support therapy (MOST) as three arms
of sepsis management. The immune system is a complex network and the immune response
to pathogens relies both on innate and adaptive components. When a local response escalates
into a systemic immune response, activation of several signaling pathways on different
receptors will generate a “cytokine storm”. Extracorporeal therapies (ECTs) in sepsis have a
firm physiological basis. Over the years, multiple extracorporeal techniques have evolved, with
the intent of influencing the circulating levels of inflammatory mediators like cytokines and
chemokines, the complement system, as well as factors of the coagulation system.
Sepsis is the leading cause of morbidity and mortality in critically ill patients. The treatment
of sepsis remains a challenge for clinicians. Dysregulation of the immune response is now
shown to be a key pathobiology phenomenon in multiple organ dysfunction, yet therapy
for inflammation remains inconclusive and ineffective. Newer treatment modalities in the
form of adjuvant therapies targeting the inflammatory cascade needs to be explored further.
However, human trials using adjuvant strategies have been disappointing, largely because of
the enormous complexity of the pathogenesis of sepsis, and the futility of attempts to block a
single inflammatory mediator, while ignoring the complex interplay of different biologically
active cellular and humoral mediators. Extracorporeal therapies (ECTs) such as hemo(dia)
filtration, plasma exchange, and specific cartridges have evolved. The physiological basis for
using such therapies in sepsis is strong. Multiple extracorporeal techniques have evolved, with
Chapter 22  Extracorporeal Therapies in Sepsis 169
Flowchart 1: Sepsis—the final common pathway.

the intent of influencing the circulating levels of inflammatory mediators like cytokines and
chemokines, the complement system, cellular cascade as well as factors of the coagulation
system. Judicious patient selection for extracorporeal therapies is based on objective and
subjective criteria. Physiological derangements, biomarker kinetics, disease dynamics are
major factors influencing decision. Right patient selection and timing of therapy remains
very important in optimizing outcomes in a cost-effective manner. A frequently reported
clinical effect has been the stabilization of hemodynamics and mean arterial blood pressure
and improvements in oxygenation indices. Multiple options are available, which essentially
have same mechanism of action with intricate technical differences. The understanding about
various available options is growing and the evidence is evolving.
“Except on few occasions, the patient appears to die from the body’s response to infection rather
than from it.” Sir William Osler, 1904

NEED FOR EXTRACORPOREAL THERAPY IN SEPSIS


Sepsis is characterized by a cytokine network that is synergistic, redundant, autocatalytic, and
self-augmenting. The control of such a nonlinear system cannot be approached by simple
blockade or elimination of some specific mediators. Nonspecific removal of a broad range of
inflammatory mediators by high-volume hemofiltration (HVHF) and coupled plasma filtration
adsorption (CPFA) may be beneficial. The nonselective control of the peaks of inflammation
and immunoparalysis may contribute to bring the patient to a lesser degree of imbalance and
close to the self-defenses induced by a nearly normal immunohomeostasis (Fig. 1).
Various approaches have been tried in past to serve as adjuvant therapy in sepsis, but were
lost to larger body of evidence which emerged in subsequent years. This is largely explained by
redundancy and pleiotropia of sepsis mediators. Redundancy means that if we block, e.g. the
tumor necrosis factor, the IL-6 is still active and leads—on a parallel way—to the same damage.
Pleiotropia means that each mediator has variable effects, which could be contrasting. Thus,
the reasons for failure of all these monocausal treatments is that there is no single lethal factor,
and as long as we do not know the exact immune status of the patient, it might be dangerous
170 Section 1  Renal Replacement Therapy

Fig. 1: Role of ECT as adjuvant therapy for sepsis.


(ECT: extracorporeal therapy)

to block only one of these mediators. A therapy is desired, which blocks the septic cascade by
different mechanisms without influencing beneficial physiological functions.
The lack of survival advantage with most of adjuvant therapies prompted many researchers
to call clinical sepsis research as graveyard of sepsis research. So, sepsis remains largest unmet
ICU need.
Over four decades, numerous trials and adjuvant therapies are tried in critically ill patients
with sepsis. We need a novel antiendotoxin neutralization therapy. But why do we need
immunotherapy? We know sepsis as a generalized inflammation, and inflammation is an
immunological event. What we really desired was a drug, which blocks the septic process by
different mechanisms without impairment of physiological functions. Understanding the fact
that there is a need for another causal treatment besides antibiotics, clinicians and industry
developed new additional approaches for the different levels of the septic process.
Extracorporeal therapies and immunomodulation using continuous renal replacement
therapy (CRRT) are promising adjuvant therapies. The various techniques include hemodialysis
(diffusive), hemofiltration (convective), hemodiafiltration (mixed), adsorbents, and plasma
filtration.2 Convective modalities have the advantage of removing higher-molecular weight
substances, which include many inflammatory mediators. The removal of the broad spectrum
of pathogenic molecules identified in sepsis is the biological rationale and theoretical basis of
extracorporeal therapy (ECT) in sepsis.

IMMUNOHOMEOSTASIS
There has been a widespread tendency to target only pro-inflammatory mediators with ECT
rather than to attain immunohomeostasis. The aim is to bring the system to lesser degree of
immune dysfunction. The therapy should focus more precisely on a balancing hypothesis
trying to restore a correct equilibrium between immune suppression and activation. The later
Compensatory Anti-inflammatory Response Syndrome (CARS) phase predisposes the patient
to infection and second hit of sepsis.
Chapter 22  Extracorporeal Therapies in Sepsis 171
A relative immunosuppression is observed in patients after sepsis, trauma, burns, or any
severe insults. It is currently proposed that selected patients will benefit from treatment aimed
at boosting their immune systems. This widens the indication of ECT covering both systemic
inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response
(CARS) phases. However, the host immune response needs to be considered contextually with
pathogen type, timing, and mainly tissue specificity. Indeed, the immune status of leukocytes
is not universally decreased and their activated status in tissues contributes to organ failure.

ADJUVANT THERAPIES
The options for adjuvant therapies in sepsis are ulinastatin, IgM-enriched immunoglobulin
,and various ECT. Some adjuvant interventions are targeted to attenuate the danger-
associated molecular pattern (DAMP) based overwhelming pro-inflammatory forces (i.e.
cytokine adsorption), while other interventions boost immunological defense against the
invading pathogens (i.e. ulinastatin, IgM-enriched immunoglobulin). It is reasonable to
remove and/or antagonize endotoxin when treating patients with sepsis and septic shock.
Removal of lipopolysaccharides (LPS) or other microbial constituents can be by filtration or
absorption (columns, polymyxin B). The removal could be nonspecific as with CPFA or with
specific modalities like polymyxin direct hemoperfusion (PMX-DHP). Target inflammation
with avoidance of further activation of clotting factors is desired in sepsis. ECT may provide
benefits to septic acute kidney injury (AKI) patients.

Threshold Modulation Theory


Threshold modulation theory elaborately elucidates cytokine system in a very dynamic and
comprehensive form. Mediators of sepsis are extricated from body to change tissue cytokine
concentrations but blood level might not need to fall. Pro-inflammatory cascade is halted
and controlled when cytokine levels fall to “threshold” level. Mediator delivery theory is the
basis for HVHF. Higher incoming fluid volumes (3–6 L/hr) augment lymph flow by about
20–40 times causing “Drag” of mediators and cytokines with lymph circulation. This lymphatic
pull drags cytokines from tissues to blood and fastens extracorporeal retrieval leading to fall in
tissue levels.

RATIONALE FOR ENDOTOXIN REMOVAL


Endotoxin is the outer membrane of Gram-negative bacteria interacting with the host during
Gram-negative sepsis. High levels of endotoxin activity correlate with severity and an increased
risk of dying while in the ICU. Endotoxins are detectable in most septic patients; high levels
associated with shock and lethality. There is strong evidence that the septic state is due to a
combination of direct and indirect effects of endotoxins. Thus, removal of endotoxin is hoped
to improve outcome in sepsis. Targeting endotoxin early in the sepsis, clinical presentation
could help reverse or limit this disease before the cascade reaction becomes overwhelming.
A cytokine storm or hypercytokinemia is a potentially fatal immune reaction with a positive
feedback loop between cytokines and cellular cascade, with highly elevated levels of various
cytokines. Attenuating the cytokine storm in the early phase of critical illness may provide
some benefits by counterbalancing the overwhelming pro-inflammatory response.
172 Section 1  Renal Replacement Therapy

Options for clearing “septic solutes”:


■ Renal replacement therapy (RRT), HVHF, CPFA
■ High cutoff membranes
■ Sorbents
■ Inhibit endotoxin activity with antagonistic synthetic partial endotoxin structures
■ Neutralization by ulinastatin and immunoglobulins
■ Direct hemoperfusion with polymyxin B-immobilized fiber column.

CONTINUOUS RENAL REPLACEMENT THERAPY IN SEPSIS


Lack of specificity of removal of mediators and inhibitors of sepsis remains the biggest
challenge. Few studies have shown beneficial clinical effects with no change in cytokine levels.
CRRT may not only be supportive but rather therapeutic. Conventional CRRT (conventional
filters and flow rates) has shown suboptimal clinical benefits in sepsis.

SPECIFIC EXTRACORPOREAL CIRCUITS FOR SEPSIS


Blood purification techniques including hemoperfusion, plasma exchange, and hemofiltration
with hemoperfusion are associated with lesser mortality as shown in a recent meta-analysis.3
Removing endotoxin would be an effective adjuvant approach in the management of sepsis.
Over the last decade, multiple extracorporeal techniques have evolved with the intent of
influencing the circulating levels of different inflammatory mediators.
The IMPACT system removes cytokines, endotoxins, bilirubin, and many other mediators
of sepsis with three different filters. The main focus of CytoSorb therapy is the removal of
inflammatory mediators, particularly cytokines, and chemokines. The CytoSorb adsorber
removes a wide range of pro- and anti-inflammatory mediators between a 5 kDa and 60 kDa
molecular weight range, where most cytokines belong. Polymyxin direct hemoperfusion (PMX-
DHP)-polymyxin B has been fixed and immobilized with polystyrene fiber in a hemoperfusion
column polymyxin B-immobilized cartridge (toraymyxin 20-R) that allows endotoxin
removal.4,5 LPS adsorber contains a series of porous polyethylene plates covered with a peptide
specific to endotoxin and with high adsorption capacity. OXiris is AN-69 (polysulfone and
polyacrylonitrile)-based membrane that adsorbs a large range of inflammatory mediators
such as endotoxin and cytokines.6
MATISSE is based on the endotoxin-binding abilities of human albumin; this adsorber
contains human serum albumin immobilized on polymethacrylate beads.7

Judicious Patient Selection for Extracorporeal Therapies in Sepsis


The evidence for different specific cartridges used with ECT is emerging. ECT has evidence
in endotoxin removal and clinical utility in management of critically ill septic patients. The
physiological basis is strong with favorable clinical outcomes. There are multiple options
available to the clinicians to choose from. However, selection criteria and outcomes need to be
judiciously understood.
The question remains why and when should we commence these therapies, if we do
it at all, and which patients would benefit the most?8 The confusion regarding the sepsis
diagnosis and dynamics leaves us with obvious uncertainties. It is difficult to know for sure
Chapter 22  Extracorporeal Therapies in Sepsis 173

Box 1: Patient selection for adjuvant therapy.


Severity of sepsis:
Utilize objective and subjective criteria
Sepsis-induced organ failure: SOFA score
Biomarkers:
Physiological parameters: Perfusion, hemodynamics and oxygenation
APACHE II:
High risk of death: Any of the following:
• Refractory shock
• Sepsis-induced ARDS
No absolute contraindications
Response to standard therapies
Futility of therapy
• Weigh relative contraindications
Futility of care
Outcome parametersAPACHE II 25
• Sepsis-induced organ failure

in which patients we should start antibiotics or commence adjuvant therapies, which is still
based on the physician’s “gut feeling” rather than objective parameters during our everyday
practice.
Judicious patient selection is contextual based on severity of sepsis, timing, phase of
disease, biomarker trends, disease dynamics, risk of death, cost-effectiveness, futility of care,
and many other variables.
Before initiating ECT for sepsis, the standard care process should be thoroughly followed
and patient should be fully supported. Acute Physiology and Chronic Health Evaluation II
(APACHE II) score >20 is a good screening tool.
High risk of death can be indicated by objective as well as subjective criteria (Box 1).
No absolute contraindications should be there. Relative contraindications should be
weighed.
The use of this pre-heparinized membrane could be a simple and safe alternative to circuit
heparinization for high-bleeding risk patients.
Syndromic recognition of high-risk patient is important to justify therapy. Meningo-
coccemia, sepsis-induced acute respiratory distress syndrome (ARDS), purpura fulminans,
and refractory shock signal high mortality.
Extracorporeal therapy is an option in the profound septic shock, indicated by high
vasopressor requirement and multiple organ failure with at least two organs involved.9 No
improvement within a few hours after the commencement of resuscitation and antimicrobial
therapy should contemplate use of ECT. Procalcitonin (PCT) values remain unchanged or
increasing in addition to no improvement in clinical condition is a consideration for ECT.

Biomarker Dynamics
Biomarker-guided interventions are based on dynamic levels of various biomarkers in clinical
context. Endotoxin activity assay (EAA), PCT, TNF, IL-6, and few others have been utilized for
174 Section 1  Renal Replacement Therapy

Fig. 2: Potential “therapeutic window” as indication of adjuvant therapies.


(PCT: procalcitonin)

decision-making. Theranostics refers to specific intervention based on biomarker level. This


concept has important role in personalized medicine for sepsis. Extensive research is still
ongoing to find better biomarker to guide. However, no biomarker can answer all questions
alone with 100% sensitivity and specificity, and so no holy grail for sepsis diagnosis. PCT and
C-reactive protein (CRP) are most commonly used biomarkers. Despite their popularity, there
are still many pros and cons, with no clear answers regarding their usefulness and interpretation
in guiding adjunctive therapies. EAA has been used in many centers to guide PMX-DHP (Fig. 2).
“Sepsis at its inception is difficult to recognize but easy to treat; left unattended it becomes easy
to recognize but difficult to treat” Machiavelli

Timing of Therapy
Organ behavior and organ failure is a time function. ECT helps support failing organs and
helps strategize regeneration.

How Early is Early and How Late is Late?


Early initiation is not justified for all patients. Most patients recover with standard practices.
However, risk stratification is must in critically ill septic patients. It is difficult to correlate
the benefit in lesser critical patients. At the same time, utilizing the therapy late in refractory
shock will not benefit much. Ideal time to start adjuvant therapy cannot be precisely defined.
A consideration should be given as early as possible after the onset of septic shock and even
earlier in few selective high-risk groups.

Expectations
Sepsis care is comprehensive and no therapy can save life alone. ECT helps cut sepsis cascade,
which should translate into improvement of hemodynamics and oxygenation indices.
Chapter 22  Extracorporeal Therapies in Sepsis 175
Survival benefit as an end point in this context is difficult to achieve. The larger trials should
focus on surrogate end points. Lesser immune dysfunction leads to lesser organ dysfunction
and improvements in perfusion and oxygenation indices. ECT as adjuvant to conventional
medical care is effective in improving clinical outcomes in a selective critically ill patient
subset diagnosed with sepsis.
Adjuvant therapies are promising showing clinical plausibility. However, in this era of
evidence-based medicine, they pose a difficult challenge of proving significant survival
benefit. In the world of evidence-based medicine, adjuvant therapies have a very difficult task
to prove themselves. Mainly single-center or small trials show therapeutic benefit on outcome
and these positive results are often reversed by larger multicenter trials. Nevertheless,
from a pathophysiological point of view, most of these therapeutic modalities have a firm
pathophysiological rationale. ECTs for sepsis are often limited with limited evidence. However,
it is important to acknowledge that “absence of evidence” should not translate into “evidence
of absence”.
Extracorporeal therapy controls the cascade and provides a window of opportunity for
organ regeneration and improved physiological variables.10 There might be a need to repeat
the therapy in some patients. This again should be contextual and guided by clinical indices
and biomarkers.

FUTURE OF EXTRACORPOREAL THERAPY


Last two decades have seen tremendous innovation in the development of techniques to alter
the blood composition of patients with sepsis through ECT. The desire has been to create a
more favorable environment, with precise control on sepsis mediators allowing patients to
overcome sequel of sepsis cascade. Multimodal, individualized approach may help us to tailor
these therapies better. The “multimodal” approach means that many clinical and biochemical
parameters are taken into account simultaneously, whilst “individualized” refers to the
interpretation of changes/kinetics of certain parameters such as PCT, rather taking only “fixed”
absolute values into account. Considerable work remains in order to find and optimize the best
blood purification strategy for treatment of sepsis. If ECT has a clinically relevant effect, once
the technology and doses are right and the appropriate large trials have been completed, such
effect may be well appreciated. Theranostic circuit devices (TCDs) consist of extracorporeal
circulation and the use of an inline imaging system with a therapeutic cartridge component.
Technical understanding might provide best time frame to use various cartridges.

Available Options and Evaluation of Evidences


Removing endotoxins:
■ Toraymyxin® (Toray, Tokyo, Japan): It was one of the most widely used endotoxin removal
therapy. It uses polymyxin-B immobilized fiber column to filter out endotoxins (released
by Gram-negative bacteria). Although recently concluded studies failed to show any
mortality benefit,11 many small studies comparing polymyxin-B endotoxin adsorption to
conventional management suggest some benefit in specific subset of patient population
with severe sepsis (previous definition), high endotoxin activity or with specific genetic
profile.12,13
176 Section 1  Renal Replacement Therapy

■ The Alteco® LPS adsorber (Alteco Medical AB; Lund, Sweden): It uses a synthetic peptide
which is embedded on filter membrane for endotoxin filtration. Few small case series
reports reduced endotoxin levels and hemodynamic support.14-16 However, only multicenter
RCT (ASSET trial) evaluating its role in abdominal septic shock was terminated early due to
recruitment issues.17

Removing cytokines:
■ High-volume hemofiltration: A modality using CRRT with a high ultrafiltration rate (>50
mL/kg/hr) gives advantage of removing lipophilic middle molecules.18 Some studies show
improving hemodynamic parameters and reduced mortality,19-22 whereas a large RCT
(IVOIRE) evaluating the concept and compared high vs low-volume ultrafiltrate during
HVHF failed to show any mortality and hemodynamic benefit of large volume HF23 and the
same is confirmed in meta-analyses.24,25
■ Coupled plasma filtration and adsorption: Where plasma is first separated from blood and
then adsorption is performed over special adsorption membranes it is then returned to
blood and whole blood then moved for conventional hemofiltration. This strategy evaluated
in COMPACT-1 and COMPACT-2 trials, where there was some promising result in 1st trial
but later 2nd trial was terminated prematurely due to adverse events.26 And hence it was
described as not a suitable option for septic shock.
■ The CytoSorb® technology (CytoSorbents, Monmouth Junction, NJ, USA): This is a
hemoperfusion cartridge with specially designed polymers to adsorb all (pro and anti)
inflammatory mediators and it does not have any effect on endotoxin levels.27 Laboratory
studies show that this column is able to remove all types of cytokines (large and small),
myoglobin, PAMPs, DAMPs, bilirubin, and bile acids.28,29 But in humans, till now no
study shows convincing results with this approach.30,31 Even a recent large RCT failed to
demonstrate reduction in target cytokines over time.32

Removing cytokines and endotoxins:


■ AN69 membrane (1969, France): It is composed of a copolymer of acrylonitrile and
sodium methalylsulfonate, where the sulfonate groups render high negative charge to
membrane and so it is able to adsorb the cytokines with their cationic residues. A study
supported this hypothesis,33 but contact of blood with membrane-induced bradykinin
generation, and was found to be responsible for hypotension in patients treated with
angiotensin-converting enzyme (ACE) inhibitor.34,35
■ The oXiris® hemofilter (Baxter, Meyzieu, France): Developed as a superior version of the
AN69ST membrane, oXiris® membrane is pretreated with nearly 4,500 UI/m2 heparin
during manufacturing while AN69ST needs a priming with a heparin. High amount
of positive charge on membrane confers capacity to absorb endotoxins. The oXiris®
membrane is made up of three layers, and its design combine four properties in one
device—anticoagulation, renal support, endotoxin, and cytokine removal. One study
comparing toraymyxin, cytosorb, and oxiris found high endotoxin and cytokine filtration
capacity as toraymyxin and cytosorb, respectively.28 A couple of RCTs are underway to
see the overall effect of this device in patient management and the promises it made in
laboratory studies and will decide the future of this device.
Chapter 22  Extracorporeal Therapies in Sepsis 177
Acting at the cellular level
■ The Seraph® 100 Microbind® (ExThera Medical, Martinez, CA, USA): It is a recently
developed affinity apheresis treatment. It uses heparin columns.
The principle behind this is that glycosaminoglycan (on human cells like heparan sulfate)
which is the pathogenic target for binding is similar to heparin present in this membrane,
and it is expected to bind in a similar way. Pilot studies are confirming that these are able to
bind various pathogens such as viruses, Gram-negative and Gram-positive bacteria, drug-
resistant bacteria, and also cytokines.36,37
■ The Hemopurifier® (Aethlon Medical, San Diego, CA, USA): It is a unique device claiming to
remove viruses from blood. First it separates plasma and in second step captures viruses.
It uses agents with high affinity for ubiquitous glycoproteins (shared on the surface of
enveloped viruses) such as lectin protein on the membrane. This therapy has already been
successfully used to treat a patient with severe Ebola virus disease.38

SUMMARY
Sepsis burden is huge with failures and mortality. ECT works by modulating the cytotoxic
and cytokinetic effects of inflammatory mediators. Many experimental and clinical studies
have provided promising results showing that blood purification therapies are well tolerated,
effective in clearing inflammatory mediators or endotoxins (or both) from the plasma, and
responsible for an improvement of different physiologic parameters (hemodynamics and
oxygenation). Judicious patient selection and right timing is essential for optimal results. In
the context of limited resources and growing expansion in the availability of technologies, a
better understanding of these therapies is required before they can be properly integrated into
standard clinical practice in the hope of influencing major clinical outcomes.

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17. Lipcsey M, Tenhunen J, Sjölin J, et al. Abdominal Septic Shock-Endotoxin Adsorption Treatment
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18. Kellum JA, Johnson JP, Kramer D, et al. Diffusive vs. convective therapy: effects on mediators of
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19. Cole L, Bellomo R, Journois D, et al. High-volume haemofiltration in human septic shock. Intensive
Care Med. 2001;27(6):978-86.
20. Honore PM, Jamez J, Wauthier M, et al. Prospective evaluation of short-term, high-volume
isovolemic hemofiltration on the hemodynamic course and outcome in patients with intractable
circulatory failure resulting from septic shock. Crit Care Med. 2000;28(11):3581-7.
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hemofiltration during refractory severe septic shock. J Trauma Acute Care Surg. 2012;72(5):
1228-38.
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23. Joannes-Boyau O, Honoré PM, Perez P, et al. High-volume versus standard-volume haemofiltration
for septic shock patients with acute kidney injury (IVOIRE study): a multicentre randomized
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Chapter 22  Extracorporeal Therapies in Sepsis 179
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during sepsis-a review of the literature. Int J Artif Organs. 2017;40(5):205-11.
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device on IL-6 elimination in septic patients: a randomized controlled trial. PLoS One.
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rats. Crit Care. 2002;6(5):429-33.
34. Renaux JL, Thomas M, Crost T, et al. Activation of the kallikrein-kinin system in hemodialysis: role
of membrane electronegativity, blood dilution, and pH. Kidney Int. 1999;55(3):1097-103.
35. Verresen L, Fink E, Lemke HD, et al. Bradykinin is a mediator of anaphylactoid reactions during
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blood by heparin-functional hemoperfusion media. PLoS One. 2014;9(12):e114242.
37. Mattsby-Baltzer I, Bergstrom T, McCrea K, et al. Affinity apheresis for treatment of bacteremia
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Biotechnol. 2011;21(6):659-64.
38. Büttner S, Koch B, Dolnik O, et al. Extracorporeal virus elimination for the treatment of severe
Ebola virus disease-first experience with lectin affinity plasmapheresis. Blood Purif. 2014;38(3-
4):286-91.
CHAPTER 23
Renal Replacement Therapy in Children
Anil Sachdev, Kanav Anand

INTRODUCTION
Acute kidney injury (AKI) is increasingly recognized as an important and independent risk
factor of morbidity and mortality in critically ill children. Despite advances in therapy, the
mortality due to the condition is still high (30–40%) and a proportion of patients may progress
to chronic kidney disease with dialysis dependency. AKI usually occurs in patients with
previously normal renal functions, but may occasionally be superimposed on preexisting renal
disease (acute on chronic kidney disease).

ACUTE KIDNEY INJURY CLASSIFICATION


Pediatric AKI can be classified on the basis of pRIFLE (pediatric Risk of renal dysfunction,
Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage kidney
disease) and pediatric renal angina criteria.
pRIFLE classification is a modified RIFLE criteria for critically ill children with AKI
(Table 1). This modification takes into account the expected normal changes in serum
creatinine concentrations that accompany somatic growth, hence more applicable for the
pediatric patients.
Pediatric renal angina criteria are based on the presence of established AKI risk factors (e.g.
mechanical ventilation, history of cardiopulmonary bypass, and bone marrow transplantation)
and evidence of renal disease (fluid overload and changes in serum creatinine). The proposed
renal angina criteria stratify patients into moderate risk, high risk, and very high risk, according
to their underlying clinical conditions (Table 2).

INVESTIGATIONS
The suggested investigations in pediatric patients with AKI are mentioned in Box 1.
Chapter 23  Renal Replacement Therapy in Children 181

Table 1: pRIFLE criteria.


pRIFLE criteria Estimated CrCl (Schwartz) Urine output
R (risk) Decrease by 25% <0.5 mL/kg/hr × 8 hr
I (injury) Decrease by 50% <0.5 mL/kg/hr × 16 hr
Early
Decrease by 75% or <35 mL/ <0.3 mL/kg/hr × 24 hr or
F (failure)
min/1.73 m2 anuria for 12 hours
L (loss) Renal failure > 4 weeks
Late
E (end stage) Renal failure > 3 months

(pRIFLE: pediatric risk of renal dysfunction, Injury to the kidney, failure of kidney function, loss of kidney
function, and end-stage kidney disease; CrCl: creatinine clearance by Schwartz formula [k × height (cm) /
serum creatinine (mg/dL)], where “k” is a constant. The value of “k” is 0.34 for preterm infants, 0.45 for term
infants, 0.55 for children and adolescent girls and 0.70 for adolescent boys.)

Table 2: Pediatric renal angina criteria.


Level of risk based on clinical status Renal angina threshold
Moderate-risk patients
Patients admitted to PICU Doubling of serum Cr
OR
eCrCl decrease >50%
OR
ICU fluid overload >15%
High-risk patients
Acute decompensated heart failure Serum Cr increase ≥0.3 mg/dL
Stem cell transplant recipient OR
eCrCl decrease 25–50%
OR
ICU fluid overload >10%
Very high-risk patients
Any serum Cr increase
OR
Receiving mechanical ventilation and
eCrCl decrease >25%
one or more vasoactive medications
OR
ICU fluid overload >5%
(PICU: pediatric intensive care unit; Cr: creatinine; eCrCl: estimated creatinine clearance; ICU: intensive care
unit)

MANAGEMENT
Management of a child with AKI includes proper monitoring, management of fluids and
electrolytes, hypertension, nutrition, and consideration for renal replacement therapy.

Monitoring
■ Weight record at least twice daily.
■ Hourly input-output recording.
182 Section 1  Renal Replacement Therapy

Box 1: Suggested investigations in pediatric patients with AKI.


Blood
Complete blood counts, CRP
Blood urea and creatinine
Electrolytes (sodium, potassium, calcium, phosphate, magnesium)
Blood gas analysis (pH, bicarbonate)
Osmolality
Serum albumin, SGOT, SGPT, CPK
Urine
Urinalysis (routine, microscopy and culture)
Fractional excretion of sodium
Osmolality
Urine for hemoglobin, myoglobin
Radiology
Chest X-ray (for fluid overload, cardiomegaly)
Ultrasonography (for renal size, identification of any obstruction, dilatation or cystic kidneys)
Renal Doppler (for suspected arterial or venous thrombosis)
Micturating cystourethrography (if suspecting vesicoureteral reflux or posterior urethral valve)
DTPA for obstructive uropathy
ECG (for hyperkalemia)
Investigations to establish the cause
Peripheral smear examination, platelet count, reticulocyte count, blood LDH levels, stool culture (in suspected
D + hemolytic uremic syndrome)
Blood ASO, serum C3 levels, antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA)
Renal Biopsy
(AKI: acute kidney injury; ASO: antistreptolysin-O antibody; CRP: c-reactive protein; CPK: creatine phosphokinase;
DTPA: diethylenetriamine pentaacetic acid; ECG: echocardiography; LDH: lactate dehydrogenase; SGOT: serum
glutamic oxaloacetic transaminase; SGPT: serum glutamic pyruvic transaminase)

■ Hourly vitals including blood pressure and toe-core temperature gradient.


■ 6-hourly blood sugar monitoring.
■ Hourly neurological observations.
■ Urine examination, blood urea, serum creatinine, plasma bicarbonate, calcium, phosphate,
and blood counts frequency to be determined depending upon the clinical picture (may be
appropriate to perform up to every 6 hours).

Fluid Management
Many children would require a fluid bolus to differentiate prerenal from intrinsic renal failure.
One or more fluid challenges of 20 mL/kg of isotonic solution (0.9% normal saline or Ringer’s
lactate) over 30–60 minutes are used depending on the volume status of the child. Diuretics
(furosemide 2–3 mg/kg IV) may be tried if the bolus has no effect. This should normally induce
a diuresis over next 2–3 hours if renal tubular function is intact. Fluid needs to be restricted in
established oliguric/anuric renal failure. Once acute intrinsic AKI has been established then
total fluids should be restricted to 400 mL/m2 of body surface area per day plus the urine output.
Extra losses due to overhead warmers, vomiting, diarrhea, etc. need to be replaced as well.
Chapter 23  Renal Replacement Therapy in Children 183

Electrolyte Management
Sodium levels are usually low in AKI because of fluid overload. Urinary sodium should be
used as a marker for total body sodium. Sodium intake should be restricted to 2–3 mEq/kg
body weight per day, together with fluid restriction, to prevent sodium and fluid retention, and
resultant hypertension. Symptomatic hyponatremia may need to be corrected with hypertonic
saline (3%), especially if serum sodium is < 118 mmol/L.
Patients with oligoanuric AKI should not receive potassium or phosphorus unless they
exhibit hypokalemia or hypophosphatemia. Hyperkalemia is common in AKI as 90% of daily
potassium excretion is handled by kidneys. Hyperkalemia needs to be treated aggressively as
it can be life-threatening.
Hyperphosphatemia is treated with the help of phosphate binders like calcium acetate
(20–65 mg/kg/day in three divided doses), calcium carbonate (20–65 mg/kg/day in three
divided doses), and sevelamer HCl (400 mg tablets; 2–4 tablets three times a day).

Hypertension
Hypertension is commonly associated with acute glomerulonephritis and hemolytic uremic
syndrome (HUS). Drugs of choice are diuretics, calcium channel blockers or β-blockers.
Hypertensive emergency should be treated with continuous infusions of sodium nitroprusside
(0.5–8 μg/kg/min) or labetalol (0.5–3 mg/kg/hr). Salt and water restriction may be helpful.

Nutrition
Adequate nutrition in critically ill children with AKI is a crucial component of their treatment.
Adequate nutrition helps in prevention of catabolism, control of metabolic abnormalities,
early recovery and may delay or prevent the need for dialysis. Renal replacement therapy
(RRT) contributes to nutritional losses, especially amino acids and water-soluble vitamins.

Treatment of the Underlying Disease


The basic pathological process, which has caused the AKI should be targeted in order to
prevent the ongoing renal injury. The strategy would include fluid resuscitation, treatment
of infection with appropriate antibiotics, maintenance of adequate cardiac output, omission
of nephrotoxic drugs, immunosuppression for lupus and Henoch–Schönlein purpura
nephritis, managing the renal vessel occlusion, and fulguration of posterior urethral valves, if
present.

Drug Dose Modification


Drug dosing must be altered for patients with AKI, not only for avoiding kidney injury, but
also to avoid toxic accumulation of drugs and their metabolites. When glomerular filtration
rate (GFR) falls to less than 50% of normal, most of the drugs excreted by the kidney require
modifications in scheduled dosing either reduction of dosage or increasing the dosing interval.
These drug dosages need to be further modified if the patient is on RRT, depending on the
clearance characteristics of the drug by the particular RRT modality.
184 Section 1  Renal Replacement Therapy

Renal Replacement Therapy


There are various modalities of RRT available to the pediatric intensivists to support the renal
system, giving it the much needed time to recover from any injury. RRT may prevent and correct
the adverse and potentially life-threatening complications of AKI including symptomatic
uremia, metabolic and electrolyte imbalance, and severe fluid overload, thereby reducing the
mortality and duration of hospital stay of children with AKI.
The modalities available for RRT include peritoneal dialysis (PD), hemodialysis (HD), and
continuous renal replacement therapy (CRRT). CRRT can be arteriovenous or venovenous
in nature, having three different subtypes, namely hemofiltration, hemodialysis, and
hemodiafiltration.
Regardless of the modality choice, initiating RRT in a critically ill child requires collabora-
tion among the pediatric nephrologists, intensivists and other subspecialists. Early discussion
and planning facilitates the process and allows for early intervention, thereby improving
survival outcomes.

PERITONEAL DIALYSIS
Pediatricians relatively have a greater experience and comfort level with PD as compared
to other modalities of RRT. PD is a cost-effective and efficient therapy as it requires less
technological expertise and resource allocation as compared to CRRT or HD. Typical access
includes: (a) Tenckhoff catheters (Fig. 1) which can be placed by pediatric surgeons in
operation theater or bedside by means of peel off technique percutaneously (31 cm—neonates
and infants, 37 cm—small children, and 41 cm—adolescents). (b) Rigid PD catheters (Fig. 2)
can also be used if cost is an issue and requirement of PD is just for a couple of days (20 cm—
infants and 30 cm—older children).

Fig. 1: Types of peritoneal dialysis catheters (Tenckhoff type).


Chapter 23  Renal Replacement Therapy in Children 185

Fig. 2: Rigid peritoneal dialysis catheter.

Peritoneal Dialysis Prescription


■ Volume of fluid (fill volume): The range is 20–40 mL/kg. We may start from a lower volume
and gradually increase depending upon the tolerance of the child. Patients with pulmonary
compromise may worsen with increased abdominal dialysate volumes.
■ Length of time in abdomen (dwell time): Usually 30 minutes.
■ Total duration of a cycle: Run-in time 5–10 minutes, dwell time 30 minutes and outflow
time 20–25 minutes; thus, each cycle usually lasts for 1 hour.

Modifications
■ Dwell time should be shorter (20 minutes) in an infant and in hypercatabolic states. In
older children, dwell time can be increased up to 1 hour.
■ In pulmonary edema, dwell time can be shortened to 15–20 minutes and concentrated
dialysate fluid (2.5%) can be used to remove fluid rapidly.
■ In severe metabolic acidosis, neonates and children with severe lactic acidosis,
“bicarbonate-based PD” is preferred.

Monitoring
■ Vitals along with accurate input–output and weight records.
■ Color of peritoneal fluid and fibrin threads in PD drain fluid.
■ Serum electrolytes and sugar every 12 hourly.
■ Blood urea and creatinine once a day.
■ Peritoneal dialysis fluid should be sent for analysis if patient is febrile or PD drain fluid is
altered in color.

Complications
■ Insertion related:
– Bleeding: It usually diminishes with subsequent cycles. Add heparin to dialysate fluid to
prevent catheter blockage.
– Bowel perforation: Uncommon when artificial ascites is created prior to procedure. It
manifests with watery diarrhea and fecal material in dialysate effluent.
– Bladder perforation: Rare if bladder is catheterized prior to procedure.
■ Poor drainage: Catheter may be blocked with fibrin or omental plug. It can be managed by
flushing, repositioning, or removal and reinsertion of catheter.
186 Section 1  Renal Replacement Therapy

■ Leakage: Purse string suture at the entry of catheter in skin prevents it. Use smaller fill
volumes if leak is detected. Ensure all holes are intraperitoneal while inserting the catheter.
■ Abdominal pain: Pain during inflow is usually cold dialysate fluid, hypertonic solution,
excessive abdominal distension or peritonitis.
■ Electrolyte disturbances (hypokalemia and hypernatremia) and hyperglycemia.
■ Dehydration.
■ Peritonitis: It manifests by abdominal pain, cloudy peritoneal fluid containing more than
100 cells/mm3 or any number of cells with more than >50% neutrophils. Usual organisms
are Gram-positive bacteria (Staph. epidermidis, Staph. aureus). Initial treatment started
with intraperitoneal antibiotics covering for both Gram-positive and Gram-negative
organisms till availability of Gram stain or culture.
■ Respiratory embarrassment (abdominal compartment syndrome) because of
overdistension of abdomen and pleural effusion.

Contraindications
Peritoneal dialysis is absolutely contraindicated in patients with diaphragmatic defects.
It is generally not recommended in patients with recent abdominal surgery or trauma,
ventriculoperitoneal shunts, prune belly syndrome, and ventilation via the high-frequency
oscillator because of the high risk of catheter leak due to abdominal movement.

INTERMITTENT HEMODIALYSIS
Intermittent HD provides more efficient solute clearance and ultrafiltration compared with
other RRT modalities. It is best suited for hemodynamically stable patients for rapid and
accurate solute and fluid removal.
Obtaining a good vascular access holds the key to satisfactory HD initiation in children.
Double lumen temporary vascular catheters (Table 3) can be inserted bedside either in the
internal jugular vein or femoral vein. Subclavian veins should be avoided in children as far as
possible in order to preserve these vessels for future use as arteriovenous fistulas in patients
who may progress to end-stage renal disease. Semipermanent tunneled catheters can be

Table 3: Pediatric vascular catheters for hemodialysis.


Weight (kg) Catheter Maximum blood flow (mL/min)
<3 5 Fr 2 single lumen 15 cm 50–75
17 cm
6.5 Fr Double lumen 10 cm
3–15 7 Fr Double lumen 10 cm 75–100
12 cm
16–30 9 Fr Double lumen 12 cm 100–250
16 cm
>30 11 Fr Double lumen 13.5 cm Up to 350
11.5 Fr 16 cm
13 Fr 21 cm
33 cm
Chapter 23  Renal Replacement Therapy in Children 187

Table 4: Types of dialyzers used in pediatric hemodialysis.


Dialyzer Membrane Surface area (m2) Blood priming volume (mL) Blood flow (mL/min)
High-flux
FX Paed Helixone 0.2 18 30–100
FX40 Helixone 0.6 32 50–200
FX50 Helixone 1 53 100–300
FX60 Helixone 1.4 74 150–400
FX80 Helixone 1.8 95 180–510
Low-flux
F3 0.4 28 50–200
F4HPS 0.8 51 50–200
F5HPS 1.0 63 100–300
F6HPS 1.3 78 150–400
F7HPS 1.6 96 200–500
F8HPS Polysulfone 1.8 113 250–600

inserted in children by surgeons or interventional radiologists in the operating room. In


neonates, umbilical veins may be considered, if no other options are available.

Dialyzers
Two types of dialyzers are used for children depending on the indication for HD. The dialyzer
surface area should be as large as possible, but should not exceed the child’s body surface area.
High-flux dialyzer has large pores, thus allowing increased clearance of large molecules. Low-
flux dialyzer is used in routine cases of azotemia (Table 4). Extracorporeal volume (tubings +
dialyzer volume) should be less than 10% of child’s blood volume. In case it is exceeding 10%,
then the circuit can be primed with blood or 5% albumin. The filling volume of circuit used for
neonates, pediatric and adult is 34 mL, 74 mL, and 128 mL, respectively.

Hemodialysis Prescription for Children


Blood flow rate: Start with 3–5 mL/kg/min and increase to 5–7 mL/kg/min as per hemodynamic
tolerance.
Dialysate flow rate: Two times the blood flow rate. Usually flow rate is kept at 300 mL/min for
small children and 500 mL/min for larger ones.
Duration of dialysis: Average duration is 4 hours per session. Start with smaller duration in case
of very high urea levels, so as to avoid dialysis disequilibrium syndrome.
Ultrafiltration (UF): Fluid removal depends on the amount of fluid overload. Total UF should
not exceed 5% of body weight in a single dialysis session.
Anticoagulation: Unfractionated heparin is the anticoagulation of choice. Loading dose of
20–40 IU/kg followed by maintenance dose of 10–20 IU/kg/hr is prescribed. Bedside activated
188 Section 1  Renal Replacement Therapy

clotting time (ACT) monitoring is done and it is maintained between 200 seconds and 250
seconds. In children with high bleeding risk, HD can be done without anticoagulation. Normal
saline flushes can be given during the session so as to prevent circuit from clotting.

CONTINUOUS RENAL REPLACEMENT THERAPY


Continuous renal replacement therapy includes dialysis (diffusion-based solute removal)
and/or filtration (convection-based solute and water removal) treatments that operate in a
continuous mode. CRRT has off late become the primary modality of choice for the treatment
of hemodynamically unstable critically ill pediatric patients.
The extracorporeal circuit can be primed with albumin or blood if the extracorporeal
volume required for CRRT (as well as HD), particularly in infants, exceeds 10% of the patient’s
blood volume.
Careful attention must be made to medications that a patient is receiving as CRRT may
alter the clearance of these drugs, especially those that are of lower molecular weight, water
soluble and not highly protein bound.
Vascular access for CRRT is same as the one used in HD.
Continuous renal replacement therapy filters are machine specific and are available in
different versions depending on their filtration characteristics (Tables 5 and 6).

Continuous Renal Replacement Therapy Prescription


Blood flow rate: 3–10 mL/kg/min
Dose: 25–40 mL/kg/hr or 2,000–3,000 mL/1.73 m2/hr of either convective or diffusive clearance.
Ultrafiltration: Depends on patient’s hemodynamic status, volume status, and ongoing fluid
[intravenous (IV) fluids, parenteral nutrition, and blood products] requirements. Average fluid

Table 5: Pediatric filters available for PRISMAFLEX (Gambro) machines.


HF 20 M 60 M 100
Type of membrane PAES AN 69 AN 69
Surface area 0.2 m2 0.6 m2 0.9 m2
Priming volume 17 mL 42 mL 66 mL
Blood volume of set 60 mL 93 mL 152 mL
Minimal patient weight 8 kg 11 kg 30 kg
Minimum blood flow rates 20 mL/min 50 mL/min 75 L/min

Table 6: Pediatric filters available for multifiltrate (Fresenius) machine.


Type Surface area (m2) Priming volume (mL)
Ultraflux AV paed 0.2 18
Ultraflux AV 400S 0.75 52
Ultraflux AV 600S 1.4 100
Ultraflux AV1000S 1.8 130
Chapter 23  Renal Replacement Therapy in Children 189
removal should be 0.5–2 mL/kg/hr (target maximum daily fluid removal at about 10% of body
weight).
Several RRT modalities, including PD, intermittent HD, and CRRT are available to manage
pediatric patients with AKI. The selection of modality of RRT is based on patient factors (size,
underlying illness, and ability to obtain vascular access), the local expertise, experience, and
available resources.
Initiating RRT in a critically ill child requires collaboration among the pediatric
nephrologists, intensivists, and other subspecialists caring for the child. Early discussion and
planning facilitates the process and allows for more rapid intervention, thereby improving
survival outcomes.

SUGGESTED READING
1. Agras PI, Tarcan A, Baskin E, et al. Acute renal failure in the neonatal period. Ren Fail.
2004;26(3):305-9.
2. Akcan-Arikan A, Zappitelli M, Loftis LL, et al. Modified RIFLE criteria in critically ill children with
acute kidney injury. Kidney Int. 2007;71(10):1028-35.
3. Andreoli SP. Acute kidney injury in children. Pediatr Nephrol. 2009;24(2):253-63.
4. Askenazi DJ, Feig DI, Graham NM, et al. 3–5 year longitudinal follow-up of pediatric patients after
acute renal failure. Kidney Int. 2006;69(1):184-9.
5. Bagga A, Mantan M. Acute renal failure. In: Principles of Pediatric and Neonatal Emergencies, 3rd
edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2011. pp. 158-68.
6. Basu RK, Chawla LS, Wheeler DS, et al. Renal angina: an emerging paradigm to identify children
at risk for acute kidney injury. Pediatr Nephrol. 2012;27(7):1067-78.
7. Bellomo R, Ronco C, Kellum JA, et al.; Acute Dialysis Quality Initiative workgroup. Acute renal
failure-definition, outcome measures, animal models, fluid therapy and information technology
needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative
(ADQI) Group. Crit Care. 2004;8(4):R204-12.
8. Blantz RC. Pathophysiology of pre-renal azotemia. Kidney Int. 1998;53(2):512-23.
9. Devarajan P. Prevention and management of acute kidney injury (acute renal failure) in children.
[online] Available from: http://www.uptodate.com/contents/clinical-presentation-evaluation-
and-diagnosis-of-acute-kidney-injury-acute-renal-failure-in-children?source=search_result&sear
ch=acute+kidney+injury+children&selectedTitle=2%7E150. [Last accessed October, 2019].
10. Devarajan P. The future of pediatric acute kidney injury management-biomarkers. Semin Nephrol.
2008;28(5):493-8.
11. Metnitz PG, Krenn CG, Steltzer H, et al. Effect of acute renal failure requiring renal replacement
therapy on outcome in critically ill patients. Crit Care Med. 2002;30(9):2051-8.
12. Star RA. Treatment of acute renal failure. Kidney Int. 1998;54(6):1817-31.
CHAPTER 24
MCQs on Renal Replacement Therapy
Ravi Jain, Rohit Yadav, Yash Javeri

1. Various forms of renal replacement therapies use one of the following physio­
logical principles:
a. Diffusion b. Convection
c. Conduction d. Both A and B
Ans. (d) Both A and B
2. Which one is not a type of RRT?
a. IHD b. SCUF
c. CAPD d. PLEX
Ans. (d) PLEX
3. Which one of the RRT modality uses only convection as a physiological principle,
except:
a. SCUF b. CVVHF
c. UF d. CCPD
Ans. (c) UF

4. A 58­year old male patient a k/c/o HFrEF presented with acute shortness of breath
have UOP <0.5 mL/kg/hr. He was started on diuretic therapy but remained non­
responsive; his hemodynamic evaluation revealed that he has dilated IVC > 2.0 cm
just below hepatic vein and variation in diameter is minimal. Point of care USG
revealed that he has b/l pleural effusion pericardial effusion and poor LV contrac­
tility. Subsequently he was started on a CRRT modality by nephrologist. His urea
and creatinine concentration remained same after 6 hours of dialysis but significant
ultrafiltrate was drawn out, which lead to symptomatic relief for patient. One of
the following modalities was probably used for this patient:
a. SCUF b. CVVHD
c. CVVHDF d. None of the above
Ans. (a) SCUF
Chapter 24  MCQs on Renal Replacement Therapy 191
5. Sodium removal in hemodialysis is achieved primarily by:
a. Diffusion b. Convection
c. Convection and diffusion d. Osmosis
Ans. (c) Convection and diffusion
6. A 65­year male, with poor nutritional status k/c/o CKD on MHD since last 4 months
by a tunneled IJ catheter, is admitted with septic shock. He was admitted and
treated successfully with antibiotics for CRBSI. He was noted to have normal HCO3
concentration predialysis. How to approach this problem?
a. Reduce dialysate bicarbonate concentration
b. Increase blood flow rate during subsequent dialysis
c. Protein calorie and nutritional evaluation
d. None of the above
Ans. (c) Protein calorie and nutritional evaluation
7. In above patient, which of the following culture sensitivity reports compel removal
of access line (tunneled HD catheter), except:
a. CON Staphylococcus b. Gram-negative bacilli
c. Candida sp d. Staphylococcus aureus
Ans. (a) CON Staphylococcus
8. A 50­year female, with diabetic nephropathy and ESRD uses fixed dose long­
acting insulin at bedtime along with regular daytime therapy. Now she is started
on MHD since last 2–3 months for progressive renal disease. She is brought to ER
with altered sensorium and uprolling of eyeballs at home; her RBS is 50 mg% on
glucometer. Family gives history of similar episodes of lethargy and restlessness
at home, while she continues on regular diet and planned dialysis. What could be
the possible explanation for this event?
a. Net diffusive loss of glucose during MHD
b. After dialysis her peripheral responsiveness to insulin improved
c. Prolonged t1/2 of insulin in CKD
d. All of the above
Ans. (b) After dialysis her peripheral responsiveness to insulin improved
9. A 66­year male patient with CKD 5 since last few years is now on peritoneal dialysis
(PD) with a background history of CAD. He was admitted for monitoring for his
cardiac ailment. Cardiologist consulted nephrologist for extra UF removal. He was
on CAPD exchanges only thrice a day, which was increased to two­hourly short
dwell volumes of 7.5% solutions by the nephrology fellow. In morning, his serum
sodium reported to be ~160 mEq/L. The probable reason for this dyselectrolytemia
is:
a. Short dwell times of high osmotic solution lead to removal of more free water
than sodium
b. The 7.5% solution usually causes hypernatremia
192 Section 1  Renal Replacement Therapy

c. Contrast used in catheterization laboratory could be hypertonic and lead to


hypernatremia
d. None of the above
Ans. (a) Short dwell times of high osmotic solution lead to removal of more free water
than sodium
10. A 60­year male k/c/o hypertension, diabetes, admitted with CAP and septic shock.
He developed respiratory failure during the course of admission and placed on
mechanical ventilation. He is requiring multiple vasopressor support. He also
developed worsening organ function in form of altered hepatic functions and
renal dysfunction because of ATN. He is oliguric with creatinine of 3.0 mg/dL.
He has metabolic acidosis with serum bicarbonate level 16 and pH of 7.27 with
serum lactate conc of 5.0 mEq/L. What can be the best approach for his acidosis
correction?
a. Resuscitation with Ringer’s lactate solution
b. Resuscitation with 0.9% NaCl solution
c. Sodium bicarbonate replacement
d. Renal replacement therapy
Ans. (d) Renal replacement therapy
11. For above patient, what is the best approach for a hemodialysis access?
a. Right internal jugular vein b. Left internal jugular vein
c. Subclavian vein d. Femoral vein
Ans. (a) Right internal jugular vein
12. RRT can facilitate management of severe lactic acidosis by following, except:
a. Handling volume efficiently
b. Bicarbonate delivered in large quantities
c. Helps in improving survival of patient
d. Remove toxins producing severe metabolic acidosis
Ans. (c) Helps in improving survival of patient
13. Therapeutic target of base delivery for severe acidemia is a pH of:
a. >7.4 b. >7.2
c. >7.0 d. >7.3
Ans. (b) >7.2
14. When used for severe acidosis, how does the bicarbonate therapy affect calcium
concentration?
a. Total calcium concentration decreases
b. Ionized calcium concentration decreases
c. Ionized calcium concentration increases
d. No effect on calcium concentration
Ans. (b) Ionized calcium concentration decreases
Chapter 24  MCQs on Renal Replacement Therapy 193
15. Choose the best RRT for severe metformin­associated lactic acidosis (serum
lactate > 20 mEq/L):
a. Peritoneal dialysis b. Plasma exchange
c. Intermittent hemodialysis d. Continuous renal replacement therapy
Ans. (c) Intermittent hemodialysis
16. For uremic pruritus, which one of the following is not effective?
a. Pregabalin b. Gabapentin
c. Antihistamines d. Topical emollients
Ans. (c) Antihistamines
17. Not consistent with depletion of effective circulating blood volume:
a. Fractional excretion of sodium < 1%
b. A urinary sodium above 20 in a urine with an osmolality of 1,000 mOsm/kg H2O
c. Urine creatinine of 60 mg/dL with a serum creatinine of 2.5 mg/dL
d. A urine sodium of 15 mEq/L and a urine potassium of 38 mEq/L
Ans. (d) A urine sodium of 15 mEq/L and a urine potassium of 38 mEq/L
18. A patient in ICU had following laboratory values:
Na+ = 140 mEq/L K+ = 4.0 mEq/L
Cl = 110 mEq/L

HCO3− = 13 mEq/L
Albumin = 2.0 g/dL
What is the corrected anion gap (AG) for this patient?
a. 12 b. 17
c. 22 d. 26
Ans. (c) 22
19. What is the most accurate technique to measure dialysate sodium to help assist
in getting an accurate plasma sodium level during HD?
a. Flame photometry b. Direct ion-selective electrode
c. Indirect ion-selective electrode d. None of the above
Ans. (c) Indirect ion-selective electrode
20. Low­dialysate sodium lead to improvement in which of the following parameters?
a. Interdialytic weight gain b. Intradialytic hypotension
c. Predialysis systolic blood pressure d. Postdialysis blood pressure
Ans. (a) Interdialytic weight gain
21. What is reference value for anion gap in a particular patient?
a. Serum anion gap between 3 mEq/L and 9 mEq/L
b. Lowest serum anion gap in the medical records
c. Serum anion gap between 8 mEq/L and 16 mEq/L
d. Baseline patient’s serum anion gap
Ans. (d) Baseline patient’s serum anion gap
194 Section 1  Renal Replacement Therapy

22. A 75­year old male presented to triage with alleged history of ingestion of whole
strip of his aspirin tablets to ER; now he is anxious, agitated, and tachypneic.
Initial laboratory reports suggest high anion gap metabolic acidosis with respira­
tory alkalosis along with hyperlactetemia. What is the most effective treatment
for his aspirin overdose?
a. GI decontamination b. Alkalinization of urine
c. Supportive resuscitation d. Hemodialysis
Ans. (d) Hemodialysis
23. Following are dialyzable drugs, except:
a. Methanol b. Thallium
c. Valproic acid d. Tricyclic antidepressants
Ans. (d) Tricyclic antidepressants
24. Following cause metabolic acidosis in ESRD patient on dialysis, except:
a. Malnutrition b. Hypercapnia
c. Nasogastric suction d. Massive blood transfusion
Ans. (b) Hypercapnia
25. What is standard hemodialysis solution buffer?
a. Bicarbonate and chloride b. Bicarbonate alone
c. Bicarbonate and citrate d. Bicarbonate and glucose
Ans. (c) Bicarbonate and citrate
26. All of the following are recommended anticoagulation strategies for dialysis
circuit, except:
a. 1,500 IU/HR heparin prefilter+ 15 mg/hr protamine postfilter
b. Low-dose heparin < 500 IU/hr
c. Regional citrate with calcium containing dialysate
d. Low-molecular weight heparin
Ans. (c) Regional citrate with calcium containing dialysate
27. Which one of the following can be removed with filtration and dialysis both?
a. Small molecules < 500 Da and electrolyte
b. Middle molecules (medium-size molecule 500–5,000 Da, low-molecular weight
protein 5,000–50,000 Da)
c. Water
d. Inflammatory proteins
Ans. (a) Small molecules < 500 Da and electrolyte
28. Following are examples of medium­size molecules, except:
a. Vitamin B12 b. Albumin
c. β2 microglobulin d. Myoglobin
Ans. (b) Albumin
SECTION 2
Extracorporeal Membrane Oxygenation

Types of Extracorporeal Membrane Oxygenation:


‰‰ Extracorporeal Membrane Oxygenation
‰‰
Venoarterial, Venovenous and Hybrid Extracorporeal Complications
Membrane Oxygenation Charudatt Vaity, Jitendra Chaudhari, Rahul Pandit
Rajeev Gupta, Poonam Malhotra Kapoor Extracorporeal Membrane Oxygenation Weaning
‰‰
Physiology during Extracorporeal Membrane
‰‰ Sandeep Dewan, Madhur Arora, Munish Chauhan
Oxygenation Support Extracorporeal Membrane Oxygenation Carbon
‰‰
Poonam Malhotra Kapoor, Sandeep Sharan Dioxide Removal
The Extracorporeal Membrane Oxygenation Team
‰‰ Ritu Airan, Poonam Malhotra Kapoor
Composition Extracorporeal Cardiopulmonary Resuscitation
‰‰
Srinivasan Ramananthan, Ravindra Ghawat Kanwalpreet Sodhi, Gunjan Chanchalani,
Indications of Extracorporeal Membrane Oxygenation
‰‰ Anju Grewal
Sandeep Dewan, Madhur Arora, Munish Chauhan Cardiac Issues in Extracorporeal Membrane
‰‰
Know the Extracorporeal Membrane Oxygenation
‰‰ Oxygenation
Machine: Circuit and Hardware Bhanu P Zawar, Yatin Mehta
Vinod Kumar Singh Extracorporeal Membrane Oxygenation
‰‰
Cannulation, Priming and Initiation of ECMO
‰‰ for Toxicology
Manender Kumar, Sarju Ralhan, Dinesh Garg Samir Gami, Dipak Viradia, Haresh Vastarpara,
Anticoagulation during Extracorporeal Membrane
‰‰ Khushbu Vaghasiya
Oxygenation Extracorporeal Membrane Oxygenation and Renal
‰‰
Srinivas Samavedam, Rajyalakshmi B Replacement Therapy
Heparin and Alternatives for Anticoagulation in
‰‰ Anand Raghunathan, Kesava Dev, Buddhika PJ
Extracorporeal Membrane Oxygenation Samaranayaka
Muralidhar Kanchi Nutrition in Extracorporeal Membrane Oxygenation
‰‰
Monitoring during Extracorporeal Membrane Ruchira Khasne, Leena Bhangale, Mansi Dandnaik
‰‰
Oxygenation Extracorporeal Membrane Oxygenation and Sepsis in
‰‰
Vivek Gupta, Rajeev Gupta, GS Wander Intensive Care Unit
Mechanical Ventilation during Extracorporeal Subba Reddy K
‰‰
Membrane Oxygenation Extracorporeal Membrane Oxygenator
‰‰
Pradip Kumar Bhattacharya, Lata Bhattacharya as a Bridge-to-Heart Transplant
Sedation and Pain Management on Extracorporeal Sunil Karanth
‰‰
Membrane Oxygenation ECMO in Pediatric Population: Is it Different from
‰‰
Babu Abraham, Ajay Padmanaban Adults?
Transfusion Therapy during Extracorporeal Membrane Kamlesh Tailor, Nilesh Bohra, Garima Bhag
‰‰
Oxygenation Extracorporeal Membrane Oxygenation MCQs
‰‰
Parshotam Lal Gautam, Suneet Kathuria, Shikha Gupta Sandesh KJ, Yash Javeri, Deo Shankar Patel
CHAPTER 25
Types of Extracorporeal Membrane
Oxygenation: Venoarterial, Venovenous and
Hybrid Extracorporeal Membrane Oxygenation
Rajeev Gupta, Poonam Malhotra Kapoor

INTRODUCTION
Extracorporeal membrane oxygenation (ECMO) has emerged as a life-saving therapeutic
modality for seriously ill patients suffering from refractory, respiratory, or circulatory organ
failure. Clinical uses of ECMO not only minimize the risk of progressive multiorgan failure,
but also give valuable time to treating unit for important decision-making. Furthermore, with
recent advancement in technology and available evidences of improved survival with ECMO
use (Class II, Level C), its indications in numerous critical care settings are continuously
growing. Main emphasis of this chapter is to review recent indications, types of ECMO,
potential complications and their management, as well as absolute contraindications, goals to
achieve successful ECMO support.
Successful outcome of ECMO support depends upon correlation of a patient’s
pathophysiology and extracorporeal circuit design. It is important to avoid mismatch between
cardiovascular and respiratory support. ECMO circuit is designed in such a way that it fulfills
the metabolic demands through adequate cerebral, coronary, and systemic oxygenation.
Main determinants for ECMO circuit design are anatomical (arterial and vein diameter,
cardiovascular anomalies, and redosurgeries) and physiological (respiratory and/or cardiac
failure). Techniques and expertise are required for quick and easy ECMO support implementation
in case of urgent, elective extracorporeal cardiopulmonary resuscitation (eCPR). It means
institutional expertise will also influence the type of ECMO support provided and outcome.1,2
Extracorporeal membrane oxygenation configurations can be subdivided into two
categories:
1. Venoarterial (VA) ECMO
2. Venovenous (VV) ECMO.

VENOARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION


There are two different cannulation strategies for patients requiring VA ECMO:
1. Central cannulation
2. Peripheral cannulation.
198 Section 2  Extracorporeal Membrane Oxygenation

Fig. 1: Circuit diagram for venoarterial extracorporeal membrane oxygenation.


(RA: right atrium; RIJV: right internal jugular vein; FV: femoral vein; Ao: aorta; FA: femoral artery; CA: carotid
artery; RSCA: right superior carotid artery; Ax: aortic root)

In VA ECMO, venous blood is drained from the right atrium or vena cava, and simultaneously
returned to the arterial system either through peripheral cannulations (Fig. 1) via femoral,
axillary, or carotid arteries or directly into the ascending aorta, if central cannulation is used.
Oxygenation of venous blood is done through ECMO oxygenator and is delivered to an artery
with the help of centrifugal/roller pump. The ECMO circuit here is connected in bypassing
the heart and lungs. VA ECMO provides both respiratory and hemodynamic support. In cases
when ECMO is required postcardiotomy, the existing cannulas employed for cardiopulmonary
bypass can be connected from the heart-lung machine to the ECMO [open cardiopulmonary
bypass (CPB) circuit to closed ECMO circuit]. Femoral cannulation is relatively less invasive
and faster to initiate VA ECMO in case of emergency or cardiogenic shock.
During VA ECMO support, systemic oxygenation is far better in comparison to the
venovenous approach because the artificially oxygenated blood mixes with arterial blood and
directly perfuses distal organs.

Indications for Venoarterial Extracorporeal Membrane Oxygenation


The classic indication for VA ECMO is cardiogenic shock, defined by low cardiac output and
poor myocardial contractility causing tissue hypoperfusion (Box 1). During VA ECMO, blood
flows are adjusted as per the patient metabolic need (usually 80% of the cardiac output) which
will adequately perfuse the patient allow “rest” to the heart and lungs. Nonrandomized trails
suggest that use of VA ECMO support improves in-hospital survival in acute myocardial
infarction (MI) complicated by cardiogenic shock.
Fulminant myocarditis and sepsis-associated cardiomyopathy share the same etiologies of
that nonischemic cardiogenic shock. Use of VA ECMO as bridge to recovery in patients with
fulminant myocarditis may have outcomes similar to myocarditis patients without shock.3 Data
for VA ECMO in mixed cardiogenic and septic shock is not so supportive, though this advanced
cardiac support technology have a role in patients for whom life benefit outweigh the risks of
bleeding and thrombosis. Finally, VA ECMO can also successfully be used in postcardiotomy
Chapter 25  Types of Extracorporeal Membrane Oxygenation: Venoarterial, Venovenous and… 199

Box 1: Indications for venoarterial extracorporeal membrane oxygenation.


• Cardiogenic shock—with or without MI
• Fulminant myocarditis
• Pulmonary hypertension and right heart failure
• Pulmonary embolus with hemodynamic compromise
• Cardiac arrest (assisted CPR)
• Medication overdose
• Nonischemic cardiomyopathy including sepsis-induced cardiomyopathy
• Bridge to decision for transplant or VAD (LVAD/BiVAD)
• Support postcardiac surgery
• Post-heart/lung transplant for primary graft dysfunction
• Help and support potential organ donor before brain death
(CPR: cardiopulmonary resuscitation; LVAD: left ventricular assist device; MI: myocardial infarction;
VAD: ventricular assist device)

shock patients who are failed to immediately be weaned from cardiopulmonary bypass.4
In AIIMS, Delhi, we started integrated VA ECMO circuit in congenital heart disease (CHD) for
infants and our results reveal a significantly improved survival rate with the use of integrated
ECMO-CPB circuit. Early initiation of cardiorespiratory support with ECMO is better than
using it as a last resort in the management.5
More recently, patients with pulmonary hypertension and pulmonary embolism with right
heart failure were successfully treated using VA ECMO as a bridge to more definitive treatment,
such as thrombectomy, particularly at the stage of acute decompensation.6
Cardiopulmonary resuscitation using extracorporeal circulation such as VA ECMO is
known as eCPR. VA ECMO is a valuable tool to assist in restoring circulation during cardiac
arrest when used in conjunction with algorithmic life-support strategies. Results from various
studies confirmed the improved in-hospital survival and survival free of major neurologic
impairment up to 2 years, when VA ECMO is used in conjunction with CPR in highly selected
patients.7
In addition to shock, scope of VA ECMO is extending in Class IV/stage D heart failure.
Similar to its effective use in postcardiotomy shock, VA ECMO has also been used with
success in patients post-heart transplantation with primary graft dysfunction and myocardial
rejection with hemodynamic instability. In these cases, early initiation of VA ECMO has been
shown to have better patient survival rate. Despite high mortality in patients with primary
graft dysfunction, those patients who receive early support by VA ECMO, if survive past the
initial event can have comparable survival rates to transplant recipients without primary graft
dysfunction.8
Finally, VA ECMO has also been used with success as a bridge to left ventricular assist device
(LVAD) implantation or cardiac transplantation in patients with terminal heart failure. It can
also be used as a bridge to decision-making in a rapidly decompensating patient in whom
prognosis may be uncertain. The use of VA ECMO is growing in postoperative management of
LVAD patients, particularly in those with critical right heart failure. Here, the use of VA ECMO
can allow for cardiac support while the right ventricle (RV) adapts to hemodynamic changes
after LVAD implantation.9
200 Section 2  Extracorporeal Membrane Oxygenation

Potential Complications of Venoarterial Extracorporeal Membrane Oxygenation


and Management Strategies
As discussed, key to successful outcomes with VA ECMO is quick recognition and initiation
of this technology. However, utilization of VA ECMO must be carefully weighed against
associated possible complications. The most common adverse events involve bleeding and
thrombosis. Anticoagulation is a mainstay of management for VA ECMO to prevent circuit
thrombosis. Though no standard targets for anticoagulation exist, a suggested activated partial
thromboplastin time (aPTT) of 60–80 seconds is necessary to prevent circuit thrombosis. In
patients in whom the risk of bleeding may be higher, an aPTT goal of 40–60 seconds can be
used. For patients with lower anticoagulation targets, the flow through the circuit should be
kept above 1 L to reduce the chance of thrombosis.
Hemolysis, acquired von Willebrand factor deficiency, and thrombocytopenia are other
risk factors associated with prolonged ECMO support. These along with an increased risk
of disseminated intravascular coagulation and heparin-induced thrombocytopenia (with
or without thrombosis), all add to the burden of hematologic derangements for patients
maintained on ECMO. Due to the high probability for thrombus formation, knowledge of
potential intra-atrial communication sites, such as atrial septal defects or a patent foramen
ovale, is important for management of anticoagulation to ameliorate risk of stroke and
minimize consequences of thromboembolism.
Infection is also a significant complication related to the use of VA ECMO. Sterile techniques
and controlled implantation (operating room and cardiac catheterization suite) yield greater
success in comparison to emergent application. Prolonged use of VA ECMO also leads to a
greater risk of infection. This is presumed to be from a greater duration of indwelling catheters;
additionally, patients who require extended support with VA ECMO also tend to suffer from
critical illness and multiorgan dysfunction, besides exposing the patient to greater risk for
infection.10
Limb ischemia is also a well-known complication of VA ECMO. Cannula size, type,
and image-guided positioning of cannulas, additional and alternative sites for lower limb
cannulation are crucial steps to avoid limb ischemia. Clinical examination of visible parameters
such as temperature, color, capillarity of feet and leg, are necessary for quick diagnosis of limb
ischemia.
Vasopressors often used during ECMO support make difficult to feel pulsations, which
is further complicated by nonpulsatile perfusion of ECMO support. In addition to limb
ischemia, compartment syndrome resulting in muscle necrosis, acidosis, and lower extremity
amputation can also occur. The use of a reperfusion catheter to perfuse distal to the entry site
of ECMO cannulas increases the likelihood of limb preservation.11 This can be done either
via a surgical end-to-side graft from the ECMO circuit into the superficial femoral artery, or
to retrogradely perfuse lower limb posterior tibial artery can be cannulated. A chimney graft
(Dacron T-graft) can also be employed as an alternative to perfuse distal extremity.12 Recently,
use of near-infrared spectroscopy (NIRS) for early detection of limb ischemia is recommended.
Occasionally, the femoral vessels are unsuitable for cannulation for VA ECMO (e.g. patients
with severe occlusive peripheral artery disease or prior femoral arterial reconstruction).
Chapter 25  Types of Extracorporeal Membrane Oxygenation: Venoarterial, Venovenous and… 201
In such circumstances, the right common carotid artery should be considered as alternative
insertion site; this technique is associated with increased risk of a large watershed cerebral
infarction 5–10%. Other viable option is using of the axillary artery, facilitating ambulation
during ECMO. Axillary artery with side graft can cause hyperperfusion syndrome leading to
significant swelling and venous inadequacy either due to inflow obstruction or venous return
obstruction.13
Due to extended VA ECMO support, there is probability of LV distention to occur. VA
ECMO leads to high volume of afterload for the left ventricle to work against. This results in LV
distention and subsequently, cause pulmonary edema. Various strategies have been used for
enhancing LV decompression for patients on ECMO. These can include intra-aortic balloon
pumps, catheter-based pumps, creation of an atrial septostomy, or direct LV decompression
by venting the LA or LV apex, should be performed in operating room and preferably with
the use of VA ECMO in postcardiotomy shock patients. Frequent echocardiograms, daily chest
radiography, and close monitoring of hemodynamics can assist in identifying LV distention
and worsening pulmonary edema to help in timing of LV decompression (Table 1).14
There is lack of large randomized controlled trail for VA ECMO management strategies.
Most of the information available are based on case reports, institution experience, and
consensus (Table 2).
Management of ECMO requires high level of sophistication and technical skills for
continuous bedside monitoring; therefore, presence of a clinical perfusionist for oversight and
management of critically ill patient on ECMO circuit is a necessity and highly recommended.
Clinical perfusionist role is justified because of their ability to focus on ECMO-based
parameters, including anticoagulation, gas exchange targets, cardiac outputs, and circuit
temperatures, makes a great impact on patient care and outcome with VA ECMO.
Early after initiation of VA ECMO, cardiac output should be targeted toward maintaining
end-organ perfusion. Ideally, this can be achieved solely with the VA ECMO circuit by
adjusting the revolutions per minute (RPM) on the circuit in order to maximize perfusion to
facilitate recovery from the circuit. At times, supplementation with inotropes based on other
hemodynamic parameters (mean arterial pressure and systemic vascular resistance) may

Table 1: Difference between central and peripheral cannulation in venoarterial extracorporeal


membrane oxygenation.
Central cannulation Peripheral cannulation
Type (Aorta) (Femoral, carotid, and axillary arteries)
Limb ischemia No Possible
Infection High Low
Bleeding and transfusion More Less
Fast and easy Require sternotomy Yes
Mobility Require tunneling from Poor with femoral but good with axillary artery
xyphoid space Dacron graft
Insertion approach Direct Percutaneous (femoral)
Invasive High Less
202 Section 2  Extracorporeal Membrane Oxygenation

Table 2: Adverse events with different arterial cannulation techniques during extracorporeal membrane
oxygenation.
Artery Adverse events
Aorta Bleeding and dissection
Femoral artery • Harlequin syndrome
• Perforation of femoral artery
• Watershed effect
• Limb ischemia
Axillary artery Compartment syndrome, hyperperfusion syndrome, brachial plexus injury,
pericardial effusion, and axillary artery thrombosis

Carotid artery • Neurologic complications


• Embolic events

be necessary. Additionally, the majority of patients on VA ECMO will be intubated and


ventilated, particularly early after cannulation. Matching oxygenation with ventilation for
ECMO requires meticulous and frequent analysis of hemodynamics and arterial blood gases.

Cardiac Thrombosis
Retrograde blood flow in the ascending aorta results in accumulation of some amount of blood
in LV, when peripheral cannulation through the femoral artery and vein are used for VA ECMO.
Stasis of this blood can occur due to no LV ejection, which may cause cardiac thrombosis.

Harlequin Syndrome Leading to Coronary and Cerebral Hypoxia


During VA ECMO, fully oxygenated blood flow given peripherally into the femoral artery from
the ECMO circuit will preferentially perfuse the lower extremities and the abdominal viscera.
Mixed oxygenated blood ejected from the heart will selectively perfuse the heart, brain, and
upper extremities. As a result, of mixing cloud or watershed that forms in the aorta, when
retrograde flow from femoral artery mixes with poorly saturated blood due to concomitant
lung dysfunction, and ventilation setting mismatch ejected from the LV results in cardiac
and cerebral hypoxia. It could be unrecognized if oxygenation is monitored using only taking
blood samples from the lower extremity. Further arterial oxyhemoglobin saturation should
be monitored in both the upper extremity and the lower extremity. This phenomenon is
specific to femoral arterial cannulation, generally not seen with central or subclavian arterial
cannulation.15

Conclusion
Venoarterial extracorporeal membrane oxygenation is a valuable modality for supporting
patients with cardiovascular failure as a bridge to recovery or more definitive therapies.
Immediate transfer and co-management with tertiary care sites with experience in caring
for Class IV/stage D advanced heart failure patients is preferred. Management strategies and
various parameters must be carefully monitored as patients are bridged to recovery or more
definitive therapies to avoid complications (Boxes 2 and 3).16
Chapter 25  Types of Extracorporeal Membrane Oxygenation: Venoarterial, Venovenous and… 203

Box 2: Probable complications of venoarterial extracorporeal


membrane oxygenation.
• Limb ischemia
• Bleeding and coagulopathy, including hemolysis
• Thrombosis
• Infection
• Acute kidney injury
• Neurologic events
• Differential hypoxemia
• LV distension and pulmonary edema
• Perforation and hematoma
(LV: left ventricular)

Box 3: Targets for initial treatment (Adapted from Lafç, et al.)16


• Flow: 70–90 cc/kg/min
• FiO2: 60–100%
• SvO2: 70–75%
• Lactate: Up to 2 mmol/L
• SpO2: 95–100%
• pCO2: 35–45 mm Hg
• Mean arterial pressure: 60–80 mm Hg
• pH: 7.35–7.45
• Hematocrit: 30%
• Platelet count: Greater than 1,00,000
(FiO2: fraction of inspired oxygen; SvO2: mixed venous oxygen
saturation; SpO2: oxygen saturation; pCO2: partial pressure of carbon
dioxide)

VENOVENOUS EXTRACORPOREAL MEMBRANE OXYGENATION


During venovenous extracorporeal membrane oxygenation (VV ECMO), blood (deoxygenated
and/or carboxylated blood) is simultaneously drained (oxygenated and decarboxylated blood)
into the venous circulation (groin/neck). Multiple single/multiple lumen may be inserted into
the neck and/or groins for draining and returning blood. VV ECMO circuit is in series with
lungs, so there is no cannula cardiac support; it only provides respiratory support for patients
in refractory respiratory failure. Patient’s own venous return (which does not pass through
the oxygenator in the ECMO circuit) mixes with the blood passed through the oxygenator and
resultant arterial PaO2 and saturation represents a mixture of the oxygenated extracorporeal
blood and the unoxygenated venous blood that passes through the nonfunctional patient lungs.
This blood supply provides sufficient systemic oxygen delivery to support metabolism, and
the airway pressure is managed at rest settings.17 The most commonly employed cannulation
technique for VV ECMO is percutaneous insertion (Seldinger technique) of one drainage/
return cannula into right internal jugular vein and other return/drainage into either of the
femoral veins (Fig. 2). Drainage is supported by a long multistage femoral venous cannula
combined with short-length arterial return cannula usually femoral arterial cannula through
the internal jugular vein. This cannulation strategy minimizes recirculation (Box 4).18,19
Recirculation phenomenon is most commonly seen with femoral–femoral VV ECMO.
204 Section 2  Extracorporeal Membrane Oxygenation

Fig. 2: Circuit diagram for venovenous extracorporeal membrane oxygenation.

Box 4: Indications for venovenous extracorporeal membrane


oxygenation.
• Reversible respiratory failure including acute respiratory distress
syndrome (ARDS) either due to bronchopulmonary aspiration,
bacterial, viral or atypical pneumonia
• Barotrauma or acute or chronic interstitial pneumonitis
• Congenital diaphragmatic hernia
• Meconium aspiration
• Primary graft failure after lung transplant

In special circumstances, the cut-down technique is also used for venous cannulation, due
to failure to percutaneous access, if the patient has vague pulse sensation (like in CPR) and in
high-risk morbidly obese patients.
Important thing to understand is that all organs perfused with the same oxygen content
depend on VV ECMO circuit, native lung function and oxygen extraction and blood returning
from coronary sinus.20
Availability and growing experience with dual lumen ECMO cannulae, VV ECMO
become less invasive, easy and safe. This single Y-shaped cannula (dual lumen cannula) is
percutaneously placed in the internal jugular vein in such a manner that it drains deoxygenated
blood from superior vena cava (SVC) and inferior vena cava (IVC), while return lumen will
direct the oxygenated blood toward tricuspid valve.21 However, use of dual lumen cannula
has its own practical limitations and peculiar complications, such as higher pressure gradient
across the cannula, the complexity of cannula positioning, and possibility of cannula tip
dislodgement during routine nursing care.22-24
Recently, a novel dual lumen VV ECMO cannula Protek duo (Cardiac Assist, Pittsburgh,
PA, USA) is also available and used selectively. This cannula is also inserted percutaneously
into the right internal jugular vein (RIJV) but distal tip of this cannula is placed into main
pulmonary artery.
Thus, this protek duo cannula may decompress the RV in addition to providing gas
exchange.25
Venovenous extracorporeal membrane oxygenation prevents hypoxemia and hypercapnia;
manageable lower plateau pressures are possible as well as beneficial in reducing pulmonary
Chapter 25  Types of Extracorporeal Membrane Oxygenation: Venoarterial, Venovenous and… 205

Table 3: Advantages and disadvantages of single lumen and dual lumen cannula for venovenous
extracorporeal membrane oxygenation.
Dual lumen ECMO cannula Single lumen cannula for VV ECMO
Cost High Affordable
Insertion Precise skill for positioning More common
Recirculation Yes Yes
Cannula stiffness Stiff Malleable
Mobility Excellent Possible
Prone positioning Possible Difficult
Availability in India Limited Easy
(VV ECMO: venovenous extracorporeal membrane oxygenation)

vascular resistance. VV ECMO improves the hemodynamic instability associated with RV


failure (Table 3).

Potential Complications of Venovenous Extracorporeal Membrane Oxygenation


and its Management
Recirculation
Venovenous ECMO is an invasive procedure and associated with SIRS, and it in itself is a major
source of morbidity. This phenomenon is described as a part of blood of oxygenated blood
that bypasses the systemic circulation. After reinfusion, the recirculating blood is directly
suctioned back into the VV ECMO system.26 Recirculation negatively impacts the total amount
of systemic blood that is oxygenated and leads to poor lung support, and it voids the purpose
of VV ECMO or turns out to be an ineffective support.
The extent of recirculation is directly correlated to factors such as cannula type, size,
and positioning, pump speed, and blood flows.27 Additionally, the anatomy of the patient
may also influence the dynamics of flow. For instance, rotation of the neck or assuming an
upright position from supine position affects the orientation of cannulae, thereby affecting
recirculation.28
Proximity of the reinfusion and drainage ports will have a straightforward effect on the
amount of recirculation, with more amount of blood going under recirculation, if the two
ports are in closer proximity.29 In dual site cannulation, the distance between the return
and drainage cannulae should be kept at least 10–13 cm away from each other.30 In single
site cannulation, the gap between the ports is fixed, but placement of the cannula itself and
the surrounding anatomy will influence the amount of recirculation. The positioning of the
cannula can be verified using transesophageal echocardiography, if necessary combined
with saline injection.

Hypoxemia
Oxygen transport takes place across the oxygenator membrane. The diffusion of gas is
concentration dependent; higher the oxygen gradient, more efficient is the diffusion. Bigger
the surface area of gas exchange device, better is the oxygenation.
206 Section 2  Extracorporeal Membrane Oxygenation

In addition to VV ECMO circuit parameters, certain patient-related parameters play an


important role in influencing oxygenation such as cardiac output, hemoglobin content, and
tissue uptake (as indicated by venous oxygen saturation). The degree of oxygenation rendered
through VV ECMO is directly related to the amount of blood passing through the membrane
rather than sweep gas flows. During VV support, the artificial membrane oxygenator is placed
in series with the patient lungs. Higher level of oxygenation will increase the shunt fraction in
the patient lung by minimizing hypoxic vasoconstriction.30 The VV ECMO support can provide
and fulfill the systemic oxygenation demands of the patient.

Decarboxylation
Carbon dioxide (CO2) removal is also determined by surface area and the thickness of the
artificial membrane oxygenator. Decrease in CO2 transfer is a direct indication of failure of
the ECMO membrane oxygenator. Further, any rise in value of PCO2 in the arterial blood gas
(ABG) sample taken from oxygenator outlet, indicates possible loss of membrane function. The
process of gas diffusion inside the membrane oxygenator is affected by water vapor droplets
or blood in the gas part of the membrane, mainly CO2. In such circumstance, a technique of
oxygenator flushing is used in which sweep gas flows are increased temporarily for less than
a minute, while ensuring that the pressure gradient between the gas and blood phases of the
membranes is not increased, eliminating the condensed vapor droplets to exit the oxygenator
gas exhaust port of the membrane oxygenator.31,32
During VV ECMO, it is difficult to achieve full venous return because a small amount
remains in recirculation. This amount of blood is “shunted” past the VV ECMO circuit and
undergoes for gas exchange in the poorly functional patient lung. This results in a mixed arterial
saturation compromising oxygenated VV ECMO blood and poorly oxygenated “shunted”
blood. Since venous return is equivalent to cardiac output, the difference between ECMO flow
and cardiac output determines this “shunt” fraction (Qecmo/Qco) of 0.6.
Interventions to lower cardiac output may be considered. Insufficient analgesia and
shivering should be managed first to reduce cardiac output. If high cardiac output persists,
manage with mild hypothermia. Consider pulmonary vasodilators (NO/PGI2) to minimize
V/Q mismatch and convert to high flow configuration.

Excessive Pump Suction


In the event of inadequate venous return hampers the required pump flow, a “suck-down”
may occur due to higher RPM of centrifugal pump. This usually causes inlet pressures
to drop well below −100 mm Hg. The vessel wall can be sucked into the access ports of the
cannula, obstructing flow into the pump and damaging the vessel. The level of support can
drop dramatically, and erythrocytes are damaged leading to hemolysis. Furthermore, there
is risk of air embolism due to degassing.33 Pump speed should immediately be reduced to
recommended range of suction pressures and cannula position should be examined; an
increased caudal position or kinking of the drainage cannula may be the cause of the problem.
Other reasons for high venous side suction include hypovolemia, increased abdominal
pressure, and cardiac tamponade or pneumothorax.34 Even after the above mentioned factors
Chapter 25  Types of Extracorporeal Membrane Oxygenation: Venoarterial, Venovenous and… 207
are corrected or excluded and drainage problems continue to occur, best alternative is to opt
for a second drainage cannula to resolve suction problems.

Sepsis
Sepsis is a drastic condition often seen in patients with prolonged ECMO support. Analyze
and check all sources including the ECMO circuit. These are nosocomial infections that may
include pathogens such as yeast, and may not be resolved until decannulation and removal of
ECMO occur.

Weaning from Venovenous Extracorporeal Membrane Oxygenation


In case of sign of early recovery from the primary disease, the easiest technique to apply is
just decrease the sweep gas flow as well as reduce oxygen fraction in the oxygenator during
at least 2 hours, while maintaining the pump flow. In this way, no adjustments are necessary
for anticoagulation and blood flow can be maintained with minimal coagulation risks. In case
of failure, VV ECMO treatment is easily reinitiated. It is important to monitor SaO2, pCO2,
respiratory rate, and minute volume and adjust the mechanical ventilator if need arises.
Discontinuation of VV ECMO can be considered when the O2 fraction in the oxygenator is 21%
and the sweep gas flow has been minimized with acceptable mechanical ventilation settings,
followed by improved lung compliance and chest X-ray (CXR).
Echocardiography is mandatory during initiation of ECMO, cannula insertion,
hemodynamic monitoring and detecting complications during weaning, and should be
essential during monitoring for a successful ECMO run (Boxes 5 and 6).35,36

Box 5: Potential complications of venovenous extracorporeal


membrane oxygenation.
• Vessel perforation with hemorrhage
• Hypoxemia
• Decarboxylation
• Recirculation/shunting
• Excessive suction by centrifugal pump
• Clot and fibrin deposition in oxygenator
• Infection
• Incorrect location (e.g. venous cannula within the artery)
• Intracranial bleeding

Box 6: Contraindications for venovenous extracorporeal


membrane oxygenation.
• Nonpulmonary multiorgan failure
• Patients with advanced and/or irreversible diseases
• Uncontrolled sepsis
• Irreversible neurological injury
• Terminal illness or other life-limiting disease
• Malignancy
• Irreversible or end-stage heart or lung failure in patients who are
not candidates for transplant36
208 Section 2  Extracorporeal Membrane Oxygenation

Table 4: Different configuration for hybrid extracorporeal membrane oxygenation.


Types of VV
ECMO Perfusion Drainage
VV-A RFA RIJV + RFV/LFV
VV-A RFA RFV + LFV
VV-A RFA Dual lumen cannula in RIJV (SVC + IVC+ RA)
VA-V RFA + RIJV RFV
V-AV RFA + RIJV (through dual lumen cannula to RV) RIJV (dual lumen cannula in SVC + IVC)
VV-AV RFA RFV + LFV
VV-AV RFA + RFV RIJV + LFV
VVV-A RFA RIJV + RFV + LFV
(IVC: inferior vena cava; LFV: left femoral vein; RA: right atrium; RFA: right femoral artery; RIJV: right internal jugular
vein; RFV: right femoral vein; RV: right ventricle; SVC: superior vena cava)

HYBRID EXTRACORPOREAL MEMBRANE OXYGENATION


Recently, a new more complex configuration of ECMO is practically applied to overcome
shortcomings of VA/VV ECMO. It involves three/four cannulations known as high-flow ECMO,
or hybrid ECMO. In some patients, traditional VV ECMO approaches, there is a limitation as
it can assist oxygenation but only minimal support to LV. Patients treated initially with VV
ECMO for respiratory failure may frequently develop cardiogenic shock, requiring VA ECMO
support. Best example could be RV failure in a patient with pulmonary fibrosis associated with
pulmonary hypertension. Conversely, patients equipped with VA ECMO could develop deep
hypoxemia of the upper body, mainly concerning the heart and the brain. In such situations,
it is suggested to make arrangements to adopt VV and VA ECMO support together with a
triple cannulation strategy. Veno-arterial-venous (VAV) ECMO in acute respiratory distress
syndrome (ARDS) patients undergoing ECMO support results in improved survival and
reduction in associated mortality and morbidity in comparison to VV ECMO and VA ECMO
configurations alone.37
Cerebral hypoxemia-related issues in patients with cardiogenic shock on VA ECMO was
successfully treated after changing the configuration to VAV ECMO (Table 4).38
Venovenous extracorporeal membrane oxygenation reduces the return of unoxygenated
blood to the left heart because with this configuration return of oxygenated blood to the body
is split into two—(1) to the aorta and (2) to the right atrium (RA) (Fig. 3).
Since pulmonary circulation is lower resistance part of the circulation, there is a risk
of preferential diversion of split arterial return toward the lungs rather than to systemic
circulation. It requires close registering differential flows and partial occlusion of the inflow
tubing to pulmonary circulation may be needed to achieve an optimal distribution of flows
between two inflow limbs.39
However, “triple” cannulation expands the field of application but increases the complexity
of ECMO system (Fig. 4).
Chapter 25  Types of Extracorporeal Membrane Oxygenation: Venoarterial, Venovenous and… 209

Fig. 3: Hybrid ECMO (VAV).


(ECMO: extracorporeal membrane oxygenation; RIJV: right internal jugular vein; VAV: veno-arterial-venous)

Fig. 4: Hybrid VVA ECMO.


(VVA ECMO: veno-venous-arterial extracorporeal membrane oxygenation; RIJV: right internal jugular vein;
RSCA: right superior carotid artery; CA: carotid artery; Ao: aorta; FA: femoral artery; Ax: aortic root)

SUMMARY
■ Careful cannula placement technique, and close surveillance and monitoring are the
necessity for successful ECMO support.
■ In infants and pediatric patients.
■ Extracorporeal membrane oxygenation support using femoral arterial cannulation is
prone to higher risk to develop peripheral vascular complications.
■ Patients on ECMO, and in patients who are bridged to transplant following ECMO support,
restricted use of transfusion products is recommended.
■ Image-guided cannulation method is adopted for accurate positioning of the cannula
such as use of transesophageal echocardiographic, ultrasongraphic or fluoroscopy, while
cannulation is highly recommended.
■ Left ventricular distension should be dealt on time by transseptal drainage or venting
through the left ventricle or left atrium or pulmonary artery must be instituted.
210 Section 2  Extracorporeal Membrane Oxygenation

■ Selection of the return vessel (artery/vein) is extremely important to provide adequate


support to failing organs while maintaining proper hemodynamics as well as to avoid any
potential complications.
■ Consider for complex hybrid ECMO to overcome shortcomings of already running ECMO,
if required.

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32. Sidebotham D, Allen SJ, McGeorge A, et al. Venovenous extracorporeal membrane oxygenation
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34. Zwischenberger JB, Cilley RE, Hirschl RB, et al. Life-threatening intrathoracic complications during
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35. Kapoor PM. Echocardiography in extracorporeal membrane oxygenation. Ann Card Anaesth.
2017;20:S1-3.
36. Shaheen A, Tanaka D, Cavarocchi NC, et al. Veno-venous extracorporeal membrane oxygenation (V V
ECMO): Indications, preprocedural considerations, and technique. J Card Surg. 2016;31(1):248-52.
37. Stöhr F, Emmert MY, Lachat ML, et al. Extracorporeal membrane oxygenation for acute respiratory
distress syndrome: Is the configuration mode an important predictor for the outcome? Interact
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38. Werner NL, Coughlin M, Cooley E, et al. The University of Michigan experience with veno-
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Press; 2016. p. 269.
CHAPTER 26
Physiology during Extracorporeal
Membrane Oxygenation Support
Poonam Malhotra Kapoor, Sandeep Sharan

INTRODUCTION
Nowadays, vital organ function is very efficiently been taken care by the therapy of extracorporeal
membrane oxygenation (ECMO). Patient care is best undertaken, if the knowledge of
management of hemodynamic and respiratory physiology is done by skilled team of ECMO.
A particular interest will be directed on oxygenation, decarboxylation, and hemodynamics
during ECMO support, with the necessary distinctions between venoarterial (VA) and
venovenous (VV) ECMO settings.
In respiratory failure, mechanical ventilator-dependent patient management is different
from the management of ECMO. Membrane lung plays a vital role in gas exchange management
in ECMO patient. Physiology of patient to be managed on ECMO has to be well understood
which has been described in this chapter.

PHYSIOLOGY OF EXTRACORPOREAL LIFE SUPPORT


Use of mechanical devices is done to support heart and/or lung in ECMO. With circulation
and respiration supported by ECMO, damaging heart and lung treatment can be stopped
(vasopressors and high ventilator settings) while the failing organs are treated, recovered,
or can be replaced. Managing patients with ECMO is very different from conventional as
physiology of cardiopulmonary has to be well understood. This chapter includes a brief
review of normal and abnormal cardiopulmonary physiology, and the physiology related to
mechanical replacement of circulation and respiration.

Cardiopulmonary Physiology
The essentials of normal cardiopulmonary physiology are summarized in Figure 1. All
the tissues of the body function by combining substrates (food) with oxygen, producing
heat, energy, CO2, and water, this process is called metabolism. Metabolism is measured
by measuring the amount of oxygen consumed per minute, which is called VO2. The rate of
metabolism for adults at rest is 3 cc/kg/min or 120 c/min/m2 for a typical adult (children—
4 cc/kg, infants—5 cc/kg). Metabolism is controlled by a center in the brain and increases or
decreases depending on activity and other factors.
Chapter 26  Physiology during Extracorporeal Membrane Oxygenation Support 213

Fig. 1: A summary of oxygen consumption, delivery, and metabolism.


(BMR: basal metabolic rate; RV: right ventricle; LV: left ventricle)

Metabolic rate increases with moderate activity, fever, drugs, and hormones. It decreases
with sleep, paralysis, and cooling. Metabolic rate increases as much as five times in extreme
exercise. When the metabolic rate changes, the delivery of substrate and oxygen changes in
proportion, accomplished by a change in cardiac output. The amount of oxygen available for
metabolism is normally five times the amount actually used by the tissues. A complex system
of reflexes and hormones keeps this all in balance, referred to as homeostasis. The oxygen
gets into the blood through the lungs and arrives in tissues via perfusion of the capillaries.
About 20% of the oxygen is removed for metabolism; so 80% of the oxygen is still in the venous
blood on the way back to the heart and lungs. CO2 is produced during metabolism; the amount
(VCO2) is essentially the same as the amount of oxygen consumed (3 cc/kg/min). The CO2
comes out of the blood in the lungs and then exhaled. The amount of oxygen consumed and
CO2 produced is different for each organ but the average for all organs is measured by O2
and CO2 exchange in the lungs (Fig. 2). These principles apply to all ages and sizes, and size-
specific parameters are normalized to weight or body surface area (BSA). Typical adult values
are used in these examples.

Oxygen in Blood
Measurement of oxygen content is difficult to be measured directly from the blood gas machine
that has to be observed in patient on mechanical ventilation support (Fig. 3).
214 Section 2  Extracorporeal Membrane Oxygenation

Fig. 2: Oxygen delivery/consumption (DO2/VO2). Typical adult values are shown.

Fig. 3: DO2/VO2 relationships during normal and elevated metabolic rate. DO2 adjusts to changes in VO2 over a
wide range, maintaining DO2 5 times VO2. If DO2 drops below 5:1, normal aerobic metabolism continues, but if
DO2/VO2 is less than 2:1, anaerobic metabolism and shock occurs.

Oxygen delivery (DO2) primarily depends on the cardiac output of the patient. It should be
as follow the normal oxygen content, at rest is 120 CC/min/m2. Which is abbreviated as VO2. DO2
is limited primarily by cardiac output. If VO2 exceeds DO2 (or if DO2 is impaired), a higher
percent of the arterial oxygen content is removed in tissues, so the content in the venous
blood decreases from 16 cc/dL to lower levels. This is well tolerated until the DO2/VO2 ratio
is below 2:1. At that point there is not enough O2 to maintain oxygen-dependent (aerobic)
metabolism and metabolism switches to anaerobic mode, which causes exhaustion and lactic
acidosis. The VO2 becomes dependent on the supply of O2. Anaerobic metabolism is tolerated
for less than a few hours, leading to cardiovascular and metabolic collapse, if it persists
(Fig. 4).
Chapter 26  Physiology during Extracorporeal Membrane Oxygenation Support 215

Fig. 4: A simple diagram of VA ECMO is shown in a newborn.

Extracorporeal Membrane Oxygenation Circuit


Cannulation
It is most important to have proper access cannula for ECMO support. The size of cannula for
both venous and arterial is utmost important in ECMO patient. This access cannula drains
blood from the venous cannula which is directed to the membrane for proper oxygenation
and returned back through the arterial cannula.

Pumps
Pumps play a major role in directing the deoxygenated blood to the membrane and back to
patient. Pumps can be centrifugal, servo-modified roller, or peristaltic. The most commonly
used pump for longer duration is the centrifugal pump. Rupture of the circuit can occur when
the postpump pressure exceeds 300 mm Hg; so pumps are modified to prevent overpressure.
Centrifugal pumps create suction and hemolysis occurs when the suction pressure is high;
so centrifugal pumps are modified to prevent high suction membrane lungs (oxygenator).
Modern membrane lungs work by perfusing venous blood through a network of thousands of
small tubes (hollow fibers). The tubes are filled with continuously flowing gas, usually 100%
oxygen (the “sweep flow”). The hollow fibers are made of a material that allows gases (but
not liquids) to pass through the walls of the fibers. Oxygen and CO2 pass between the gas and
216 Section 2  Extracorporeal Membrane Oxygenation

blood in response to the gradient between the partial pressure differences. When the gas is
100% oxygen, the gradient driving gas transfer is from 600 mm Hg to 40 mm Hg for O2, and
45 mm Hg to 0 mm Hg for CO2. Even though the gradient is much larger for oxygen, the
solubility and diffusivity of CO2 is greater, so the amount of O2 and CO2 exchange is roughly
equal when the ratio of blood flow to gas flow is 1:1.
Oxygen transfer in membrane lungs: Membrane surface area of an oxygenator plays a
vital role to determine the efficiency of gas exchange and secondly the laminar blood flows
that passes through the oxygenator. Laminar flow is disrupted by small secondary flows as
the blood moves through the irregular blood flow path, mixing fully saturated red cells with
deoxygenated red cells. All these factors are summarized in the term “rated flow”. When
venous blood is perfused at a low flow through a membrane lung the hemoglobin saturation is
increased to 100%, and the outlet blood is 100% saturated. As flow increases, a point is reached
when the blood passes through so fast that all the red cells are not oxygenated, and the outlet
oxygenation and the outlet saturation drops below 100% saturation. The flow of venous blood
which exits the membrane lung at 95% saturation is defined as the “rated flow” (standard
venous blood is defined as Hb 12 g/dL, saturation 70%) (Fig. 5). Oxygenators for ECMO are
chosen based on the rated flow for oxygenation. The size of the oxygenator is matched to the
oxygen requirement of the patient.
The oxygenation efficiency of any membrane lung is determined by the oxygen delivered
through this membrane minus the oxygen content of the blood samples taken from the
membrane outlet. Normal DI-O is 5 cc/dL. The amount of oxygen delivered related to blood
flow for different DI-O is shown in Figure 6.
CO2 transfer: The amount of CO2 cleared by any membrane lung is the inlet minus outlet CO2
content difference (DI-OCO2). At 1:1 will be about the same is oxygen. But when the sweep
to blood flow ratio is increased to as high as 8:1 a much larger DI-O can be achieved and

Fig. 5: The concept of “rated flow”. Venous blood perfused through a lung exits at 100% saturation until a
limitation is reached and blood exits at less than 100% saturation. The capacity of membrane lungs saturation
drops below is described as “rated flow”.
Chapter 26  Physiology during Extracorporeal Membrane Oxygenation Support 217

Fig. 6: The amount of oxygen supplied by a membrane lung is the gas to blood flow ratio times the out-in O2
content difference. Blood flow is in deciliters.

Fig. 7: CO2 removed when gas to blood flow is 1 : 1, 4 : 1, and 8 : 1. Data for two membrane lungs is shown (PL1
and PL2).

much more CO2 can be removed. Therefore, when a membrane lung is used primarily for CO2
removal, high gas blood ratios are used and at lower blood flows as well as CO2 clearance is
achieved, in case of respiratory failure patients, goal is oxygenation. The sweep gas flow rate
is set by the operator, based on the desired PaCO2. These phenomena are demonstrated in
Figure 7.

Other ECMO Circuit Component


The cannulas, pump, and membrane lung are connected by conduit tubing. It might seem
desirable to have the circuit as close to the patient as possible, but usually the connection lines
between the patient and the circuit are about 6 feet long because it is easiest to care for both
the patient and the circuit when they are separated. One reason is because the pump and lung
are mounted on a bulky cart, which also carries the pump motor, a large battery, a water bath
218 Section 2  Extracorporeal Membrane Oxygenation

for circulating warm water through the heat exchanger, an oxygen tank, and gas regulator for
transport during shifting as patient with the monitors and displays. Monitors and alarms can
include venous and arterial blood gases, pre- and postpump pressures and flow, and blood
temperature. There are access sites for infusion and blood sampling.

Extracorporeal Membrane Oxygenation Circuit Physiology


The circuit blood and gas flow are set by the operator to match the needs of the patient. The
amount of O2 and CO2 transfer is estimated based on all the information above, then adjusted
to achieve the physiologic goals. Usually the circuit is set to totally support the circulation and
respiration initially, then decreased as physiologic goals are met.

Venoarterial Extracorporeal Membrane Oxygenation


In VA ECMO, there has to be support given for both heart and lungs, which is replaced by
artificial mechanical support, i.e. pump and membrane. In case of VA ECMO there is partial
support through the mechanical devices and partial through the patient heart surgery.

Hemodynamics
The hemodynamics of VA access is demonstrated in Figure 8. As venous blood is drained
from the right atrium (RA) and perfused into the aorta, the total flow remains constant but
the pulse contour decreases because there is less blood ejected from the left ventricle. When
the extracorporeal flow is 100% of the venous return, the systemic pulse contour is flat. This
is the situation in VA access for heart surgery [cardiopulmonary bypass (CPB)]. In CPB, the
superior and inferior vena cavae are occluded proximal to the drainage cannulas, so that
except for coronary sinus blood, all venous blood return to the circuit. In VA ECMO, the flow is
maintained at about 80% of venous return, so 20% passes through the heart and lungs. The best

Fig. 8: Physiology of VA perfusion. Avoid stagnant flow increases, pulmonary flow decreases and pulse pressure
and clotting in the pulmonary decreases until total extracorporeal flow is reached. During VA ECMO extracorporeal
flow is ideally at 80% of total flow in vessels and chambers of the heart, so the pulse pressure is about 10 mm Hg.
Chapter 26  Physiology during Extracorporeal Membrane Oxygenation Support 219
way to assess heart function in VA ECMO is by echocardiography. If the heart is completely
nonfunctional, all the venous return drains into the extracorporeal circuit and there is no
pulse contour. The patient is on total CPB (as during cardiac surgery). This is tolerated for a
few hours (if there is enough time to operate on the heart, then restore circulation), but in
ECMO, this leads to two problems. First, the left side of the heart gradually fills with blood
from bronchial and thebesian venous flow, this causes increased pressure in the left ventricle,
atrium, and pulmonary circulation. When that pressure reaches 20–25 mm Hg, pulmonary
edema occurs and the left ventricular (LV) becomes overdistended. This must be treated by
draining blood from the left side of the circulation into the circuit. This is done by creating
an atrial septal defect or by placing a drainage cannula in the left atrium (LA) (or pulmonary
artery). The second problem is that blood in the cardiac chambers and pulmonary circulation
will clot, even with systemic anticoagulation. This is treated by using higher levels of systemic
anticoagulation and adding urgency to going from ECMO to a ventricular assist device and
restoring pulmonary circulation.

Gas Exchange in Venoarterial Access


During venoarterial (VA) ECMO, fully saturated blood from the circuit is perfused into the aorta
and mixes with blood from the left ventricle. If the lungs are functioning well, then the mixed
blood is well oxygenated and has normal PCO2. The patient can be weaned from the ventilator
and managed awake. If the lungs are functioning poorly or not at all, the systemic blood gases
will reflect the mixture of the cardiac and extracorporeal flows, resulting in lower oxygenation
proximal to the site of mixing (Fig. 9). If the mixing is in the proximal aorta, blood to the brain
and coronary circulation is well oxygenated. In femoral artery access, the mixing takes place
in the mid aorta, so the upper body is perfused by the blood from the left ventricle. This can
result in differential circulation with the lower body perfused by fully saturated red blood while
the upper body is perfused with desaturated blue blood. This is referred to as the Harlequin
or red feet-blue head syndrome. This is demonstrated in Figure 10. The management of the
Harlequin syndrome is to perfuse some of the postoxygenator blood into the RA (combining
VA with VV perfusion). This is accomplished by inserting an infusion cannula via the jugular
vein, or by perfusion of a second lumen in the drainage line. Managing VA ECMO based on
these principles. In VA access, the parameters are monitored and VO2/DO2 is calculated from
these measurements. This information is used to adjust the ECMO variables and the patient
variables to maintain DO2/VO2 at 3:1 or higher.
■ Plan the circuit based on the best estimation of the metabolic rate (adults, 3–4 cc/kg/
min for both O2 and CO2) and the drainage flow which can be achieved from the largest
drainage cannula which can be placed. Plan for total support, realizing that there may
be some native lung function and total support may not be necessary. For a septic 80-kg
adult, you will need 5 L/min flow, and an oxygenator with rated flow over 5 L/min to supply
300 cc O2/min.
■ Maximum venous drainage gives flows requirement by the patient to maintain the pulse
contour. If the drainage cannula is large enough, total bypass (nonpulsatile flow) will result.
220 Section 2  Extracorporeal Membrane Oxygenation

Fig. 9: Venoarterial extracorporeal membrane oxygenation with jugular-carotid access.


(SaO2: oxygen saturation; BP: blood pressure; PAP: pulmonary artery; SVO2: mixed venous oxygen consumption;
SAT: saturation; DO2: oxygenation delivery; VO2: oxygen consumption; FIO2: % of gas dioxide; SVR: systemic
vascular resistance; PVR: peripheral vascular resistance)

Then decrease the flow until the pulse contour is 10–15 mm Hg. Then decrease the vasoactive
drugs to low or no levels. If there is no LV function, establish left atrial drainage.
■ When the patient is stable (usually 6–12 hours) determine the variables of O2 kinetics, using
the formulas described above. If oxygen supply is adequate (DO2:VO2 over 3), no changes
are necessary. If oxygen supply is inadequate (DO2:VO2 under 3) and the patient is anemic,
transfuse to a higher hemoglobin (12–14 g%). This will result in arterial saturation around
90% and venous saturation around 65% (DO2/VO = 3–4).
■ Continuous venous and arterial saturation are monitored to observe for the proper oxygen
supply through the membrane in case of mechanical support and native (i.e. venous
saturation) of the patient.
■ When the native heart begins to recover (pulse contour increases when flow is decreased)
turn down the flow, keeping the venous saturation > 70%. When the native heart function
is adequate, conduct a trial off bypass. When heart function is satisfactory, decannulate.

Venovenous Extracorporeal Membrane Oxygenation


In VV ECMO, the perfusate blood is returned to the venous circulation and mixes with venous
blood coming from the systemic organs, raising the oxygen content and lowering CO2 content
Chapter 26  Physiology during Extracorporeal Membrane Oxygenation Support 221

Fig. 10: Venoarterial extracorporeal membrane oxygenation with femoral-femoral access.


(SaO2: oxygen saturation; BP: blood pressure; SVO2: mixed venous oxygen consumption; SAT: saturation;
DO2: oxygenation delivery; VO2: oxygen consumption; FIO2: % of gas dioxide; SVR: systemic vascular resistance;
PVR: peripheral vascular resistance)

in the right atrial blood. This mixed blood passes into the right ventricle, the lungs, and into
the systemic circulation. VV access is achieved by draining venous blood from the inferior
vena cava (IVC) via the femoral vein and reinfusing into the RA via the jugular (Fig. 11), or by
draining from the IVC and superior vena cava (SVC) and reinfusing into the RA via a separate
lumen in a double lumen cannula (Fig. 12).

Hemodynamics
Hemodynamics during VV access is normal. Since the volume of blood removed is exactly
equal to the volume of blood reinfused; there is no net effect on central venous pressure,
right or left ventricle filling, or hemodynamics. The content of oxygen and CO2 in the patient’s
arterial blood represents that of right ventricle blood modified by any pulmonary function
that might exist. The systemic blood flow is the native cardiac output and is unrelated to the
extracorporeal flow.

Gas Exchange in Venovenous Extracorporeal Membrane Oxygenation


In VV ECMO, some of the systemic venous return is drained to the ECMO system, oxygenated,
and returned to the RA. Some of the systemic venous return goes directly to the RA, where it
222 Section 2  Extracorporeal Membrane Oxygenation

Fig. 11: Venovenous extracorporeal membrane oxygenation for respiratory support. Two-cannula access.

Fig. 12: Venovenous extracorporeal membrane oxygenation with a double lumen cannula.
Chapter 26  Physiology during Extracorporeal Membrane Oxygenation Support 223
mixes with the ECMO perfusate blood. The mixed blood passes through the right ventricle,
native lungs, left heart, and into the systemic circulation. In severe respiratory failure, the
native lungs contribute little or none to gas exchange, so the arterial oxygenation and CO2 is
the result of mixing the oxygenated ECMO blood with the deoxygenated native venous blood.
As a result, the arterial saturation ranges from 60% to 90%, depending on the relative amount
of ECMO flow, native venous flow, lung function, and cardiac output. The desaturated arterial
blood results in normal systemic oxygen delivery as long as the cardiac output and hemoglobin
concentration (oxygen content) are adequate. These relationships are often confusing to ICU
staff because the usual goal of management is to keep the arterial saturation over 90%.

ECMO Oxygenation
During ECMO, oxygenation plays an important role. Adequacy of oxygenation to the patient
is determined by the venous saturation and membrane oxygenation is determined by the
saturation, i.e. blood gas analysis done on postmembrane oxygenator. Both play a vital role
in case of ECMO produced by the pump or siphon and the geometry of the cannulated vessel
(usually the vena cava or RA). Typical maximum flow at 100 cm/H2O suction for common sizes
of venous cannulas is 4–5 L per minute.
Hence, flow also plays a vital role in ECMO patient to achieve adequate oxygenation,
blood flows, hemoglobin, and oxygen content in the blood. All these parameters together are
important for ECMO success and are shown in Figure 13.

Fig. 13: Mixing of perfusate with native venous flow during VV extracorporeal membrane oxygenation (ECMO).
224 Section 2  Extracorporeal Membrane Oxygenation

Extracorporeal Membrane Oxygenation Management


when the Native Lung is Recovering
All the preceding discussion describes a situation when there is no native lung function. As
the native lung begins to recover, some oxygen and CO2 exchange will occur. The effect will
be to improve systemic arterial oxygenation and PaCO2 with no change in the extracorporeal
flow rate and hemoglobin. It is tempting to increase ventilator settings and FiO2 in order to
take advantage of this recovery, but this may add to lung injury and delay lung recovery.
ECMO is continued during rest ventilator settings, and when arterial pCO2 drops below 40,
the sweep gas to the membrane lung can be proportionally decreased. When the systemic
arterial saturation exceeds 95%, the extracorporeal flow can be gradually decreased
(changing the ratio of circuit to native venous flow). When the extracorporeal support has
decreased from total support to approximately 50%, extracorporeal support can be briefly
discontinued (at moderate ventilator settings) to test native lung function. ECMO support
is gradually discontinued when native lung function is sufficiently supporting the ECMO
patient. As weaning from ECMO is very crucial, it has to be taken care that the support is
discontinued gradually. Putting the patient again on ECMO, once weaned off is not good,
as there are deleterious effects of it. Vascular access in ECMO can be difficult, it is wise to
continue ECMO support for a day or two beyond this point to allow more lung recovery,
unless there is a pressing reason to take the patient off ECMO [systemic bleeding or central
nervous system (CNS) complications].
Managing VV ECMO based on these principles: In VV access, the parameters described in
Figures 11 to 13 are monitored and VO2/DO2 is calculated from these measurements.
That information is used to adjust the ECMO variables and the patient variables to maintain
DO2/VO2 at 3:1 or higher.
■ As in VA access, plan the circuit based on the best estimation of the metabolic rate (adults,
3–4 cc/kg/min for both O2 and CO2) and the drainage flow which can be achieved from the
largest drainage cannula (or cannulas) which can be placed. Plan for total support, realizing
that there may be some native lung function and total support may not be necessary. For a
septic 80-kg adult, you will need 5 L/min flow and an oxygenator with rated flow over 5 L/
min to supply 300 cc/O2/min.
■ On ECMO, go to the highest flow to determine the maximum drainage capacity, then
turn down the ventilator to rest settings (FiO2 0.3, CPAP 15–20 cm H2O) and wean off the
vasoactive drugs. The hypermetabolism will decrease to baseline. The lungs may go to total
consolidation. Adjust the sweep gas to keep the PaCO2 40 mm Hg.
■ When the patient is stable (usually 6–12 hours), determine the variables of O2 kinetics, using
the formulas described above. If oxygen supply is adequate (DO2:VO2 over 3) no changes
are necessary. If oxygen supply is inadequate (DO2:VO2 under 3) and the patient is anemic,
transfuse to a higher hemoglobin (12–14 g%). If DO2 is still inadequate change the drainage
cannula to a larger size and increase flow.
■ Manage the patient based on continuous venous and arterial saturation monitoring.
Plot the position on Figure 4 frequently. Calculate the variables if oxygen supply seems
excessive or inadequate.
Chapter 26  Physiology during Extracorporeal Membrane Oxygenation Support 225
■ When the native lung begins to recover (the arterial saturation is >95%) turn down the flow,
keeping the venous saturation >70%, and the sweep flow, keeping the PaCO2 at 40. When
native lung function is adequate, trial off ECMO and then decannulate.

SUMMARY
Understanding cardiopulmonary physiology plays a vital role in management of ECMO patient
and thorough understanding of the ECMO circuit. Based on this understanding, the ECMO
system is used to replace part or all of heart and lung function, maintaining normal systemic
physiology while the damaged organs can recover or be replaced.

SUGGESTED READING
1. Brodie D, Bacchetta M. Extracorporeal membrane oxygenation for ARDS in adults. N Engl J Med.
2011;365(20):1905-14.
2. Feihl F, Broccard AF. Interactions between respiration and systemic hemodynamics. Part II:
practical implications in critical care. Intensive Care Med. 2009;35(2):198-205.
3. Feihl F, Broccard AF. Interactions between respiration and systemic hemodynamics. Part I: basic
concepts. Intensive Care Med. 2009;35(1):45-54.
4. Funk DJ, Jacobsohn E, Kumar A. Role of the venous return in critical illness and shock: Part
II-shock and mechanical ventilation. Crit Care Med. 2013;41(2):573-9.
5. Funk DJ, Jacobsohn E, Kumar A. The role of venous return in critical illness and shock-part I:
physiology. Crit Care Med. 2013;41(1):255-62.
6. Gelman S. Venous function and central venous pressure: a physiologic story. Anesthesiology.
2008;108(4):735-48.
7. Magder S. Bench-to-bedside review: an approach to hemodynamic monitoring—Guyton at the
bedside. Crit Care. 2012;16(5):236.
8. Mayette M, Gonda J, Hsu JL, et al. Propofol infusion syndrome resuscitation with extracorporeal
life support: a case report and review of the literature. Ann Intensive Care. 2013;3(1):32.
9. Sakamoto K, Saku K, Kishi T, et al. Prediction of the impact of venoarterial extracorporeal
membrane oxygenation on hemodynamics. Am J Physiol Heart Circ Physiol. 2015;308(8):H921-30.
10. Sunagawa K, Sagawa K, Maughan WL. Ventricular interaction with the loading system. Ann
Biomed Eng. 1984;12(2):163-89.
CHAPTER 27
The Extracorporeal Membrane
Oxygenation Team Composition
Srinivasan Ramananthan, Ravindra Ghawat

INTRODUCTION
Extracorporeal membrane oxygenation (ECMO) is a form of life support; however, it is neither
a treatment nor does it correct the underlying pathology. Over the years, ECMO has become a
modality of choice for patients with acute respiratory failure or refractory cardiogenic shock.
Despite its recent advances, ECMO continues to be a costly and complex form of treatment
with its potential adverse effects. Recent studies have shown that ECMO patient’s outcome
including complications and survival was related to the case load, experience, expertise, and
the infrastructure of the patient center. Hence, the extracorporeal life support organization
(ELSO) published the guidelines illustrating the institutional requirements for effective use of
ECMO.1 As per the guidelines, trained ECMO physicians are considered as one of the essential
components of a multidisciplinary team for the successful implementation of ECMO and its
follow-up.

WHY AN EXTRACORPOREAL MEMBRANE OXYGENATION TEAM?


Extracorporeal membrane oxygenation is a service that needs 24 hours a day monitoring of
the patient as well as the entire circuit. Formation of a team/program will help in the efficient
management of the patient due to the following factors:
■ Shared knowledge
■ Improved skill sets
■ Specialized personnel with facilities
■ Easily transportable equipment
Figure 1 demonstrates a timeline that can be used to form an ECMO team.2

COMPONENTS OF EXTRACORPOREAL MEMBRANE OXYGENATION TEAM


An ECMO team can be divided into two sections—key personnel and supportive personnel.
Figure 2 lists the key personnel involved in an ECMO team.2
Chapter 27  The Extracorporeal Membrane Oxygenation Team Composition 227

Fig. 1: Timeline for formation of extracorporeal membrane oxygenation (ECMO) team/program.

Fig. 2: Key personnel.


(VV: venovenous; ECMO: extracorporeal membrane oxygenation; EICU: electronic intensive care unit;
VA: venoarterial)
228 Section 2  Extracorporeal Membrane Oxygenation

Key Personnel
■ Extracorporeal Membrane Oxygenation Director: A clinician is chosen to have all the
managerial and clinical responsibilities of the ECMO program. The director can be a board
certified critical care specialist or a certified cardiovascular, thoracic surgeon, trauma
surgeon, or a certified specialist with experience in ECMO support.
■ Extracorporeal Membrane Oxygenation Coordinator: An experienced intensive care
registered nurse or respiratory therapist with an intensive care unit (ICU) background or
certified clinical perfusionist with ECMO experience. The coordinator is involved in the
development of all ECMO-related protocols. This personnel will be supported by deputy
coordinators to ensure around-the-clock availability.
■ Intensivists: An experienced critical care specialist has training and experience in ECMO
cannulation, console and circuit knowledge and troubleshooting if and when the need
arises. He/she is the direct link between the patient and the ECMO team: from determining
the first indications to administering the procedure itself and troubleshooting when
required. An intensivist can be considered as an ideal ECMOlogist as he/she tend to work
in a coexisting manner with people of other expertise, which is the core requirement with
an ECMO.
■ Extracorporeal Membrane Oxygenation Specialist: An ECMO specialist should have a strong
intensive care background. He/she can undertake other roles such as ensuring adequate
anticoagulation and titrating ECMO flow and gas to ensure adequate levels of cardiac and/
or respiratory support. ECMO specialists can be nurses or can come from other specialties
such as perfusion or medical backgrounds.
■ Perfusionists: They are an integral part of an ECMO program. They are experts in the
management of extracorporeal circuits, which they acquire by working with the short-term
cardiopulmonary bypass in the operating theater. Role of a perfusionist includes priming
the ECMO circuit, initiating ECMO before handing over to the ECMO specialist/intensivist,
circuit or component replacement and transport of the patient to other areas of hospital
(e.g. CT scanner). Perfusionists should be an active part of circuit design and modifications,
equipment maintenance, and development of protocols.
■ Respiratory Therapist: A respiratory therapist should have extensive training in maintenance
of normal acid–base balance, oxygenation and oxygen delivery, ventilation, and
cardiopulmonary anatomy, physiology, and pathophysiology. Equipment troubleshooting
too should be a key attribute in the training of a respiratory therapist.
■ Cardiothoracic Surgeon/Interventional Radiologist: Cardiothoracic surgeon is usually
called upon for cannulation in case of venoarterial (VA) ECMO. Other scenarios where they
play a major role are in central VA ECMO cannulation, distal perfusion cannulation, trou-
bleshooting in case of inability to cannulate by intensivist, and decannulation of VA ECMO.
Interventional radiologist plays a role in case of delay/nonavailability of a
cardiothoracic surgeon. They too can perform/assist in primary and distal cannulation
under ultrasound guidance.
■ Intensive Care Unit Nurse: An ECMO patient is primarily managed by an ICU nurse.
The nurse should be primarily trained in ECMO patient and circuit management.
Chapter 27  The Extracorporeal Membrane Oxygenation Team Composition 229

Box 1: Support panel.


Supportive personnel
Cardiologist Infectious disease specialist
Nephrologist Physical therapist
Neurologist Blood bank
Hematologist Pathologist
Cardiac anesthesiologist Microbiologist
General surgeon

Other responsibilities include day-to-day patient care and bedside monitoring. Support is
provided by healthcare support workers. In some institutes, an ECMO nurse is allotted for
care of the ECMO circuit while the ICU nurse can concentrate on patient care.

Supportive Personnel
Although the above-mentioned personnel are the major crux of the ECMO team, they do
require the assistance of experts from different fields. List of support staff is enumerated in
Box 1.1,3

Mobile Extracorporeal Membrane Oxygenation Team


Every tertiary care hospital should consider forming a mobile ECMO team for retrieval of
patients from remote areas or intrahospital transport of patients. This team should be available
at all times and should be well equipped with all the necessary training from cannulation to
patient and circuit management.4
Components of the team will be:
■ Physicians
■ Nurses
■ Extracorporeal membrane oxygenation specialist
■ Perfusionist
■ Transport specialist
■ Necessary equipment.
With all of the above components, safe transport of patients on extracorporeal support
can be ensured for short and long distances via different modes of transport, i.e. ambulance,
airplane, or helicopter.5,6

SUMMARY
Extracorporeal membrane oxygenation is a system of care, not just a bolt-on accessory. As a
result of this, an efficient and dedicated team is a must for the implementation of an ECMO
service. Intensive care skills are crucial for safe ECMO delivery. Formation of a multidisciplinary
team can facilitate better patient outcome but can also ensure safe transport of patient on
extracorporeal support for short and long distances.7
230 Section 2  Extracorporeal Membrane Oxygenation

REFERENCES
1. ELSO Guidelines for ECMO Centers. [online] Available from: https://www.elso.org/Resources/
Guidelines.aspx. [Last accessed October, 2019].
2. Moll V, Teo EY, Grenda DS, et al. Rapid development and implementation of an ECMO program.
ASAIO J. 2016;62(3):354-8.
3. Haval SS. Extracorporeal membrane oxygenation therapy—A review. Indian J Respir Care.
2014;3(2):479-87.
4. Combes A, Brodie D, Bartlett R, et al.; International ECMO Network (ECMONet). Position paper for
the organization of extracorporeal membrane oxygenation programs for acute respiratory failure
in adult patients. Am J Respir Crit Care Med. 2014;190(5):488-96.
5. Foley DS, Pranikoff T, Younger JG, et al. A review of 100 patients transported on extracorporeal
life support. ASAIO J. 2002;48(6):612-9.
6. Lebreton G, Sanchez B, Hennequin JL, et al. The French airbridge for circulatory support in the
Carribean. Interact Cardiovasc Thorac Surg. 2012;15(3):420-5.
7. Na SJ, Chung CR, Choi HJ, et al. The effect of multidisciplinary extracorporeal membrane
oxygenation team on clinical outcomes in patients with severe acute respiratory failure. Ann
Intensive Care. 2018;8(1):31.
CHAPTER 28
Indications of Extracorporeal
Membrane Oxygenation
Sandeep Dewan, Madhur Arora, Munish Chauhan

Extracorporeal membrane oxygenation (ECMO) is a modality where venous blood from


the patient is pumped out to an extracorporeal circuit for oxygenation and carbon dioxide
removal, and then returned to the patient’s body through a vein or an artery. The two major
ECMO modalities are venoarterial (VA ECMO) and venovenous (VV ECMO).

VENOVENOUS EXTRACORPOREAL MEMBRANE OXYGENATION


Venovenous extracorporeal membrane oxygenation (VV ECMO) provides respiratory gas
exchange (oxygen loading and CO2 removal) in venous blood before it reaches the right
ventricle, and is useful in the management of severe respiratory failure when conventional
support is unsuccessful. Since blood is drained from and returned to central venous circulation,
no hemodynamic support is derived from this mode of extracorporeal life support (ECLS).
Venovenous extracorporeal membrane oxygenation system functions “in series” with the
native cardiopulmonary system. In other words, blood that is drained, undergoes gas exchange
and is returned to central venous circulation before leaving the right side of the heart.
The most common indication of VV ECMO is severe acute respiratory distress syndrome
(ARDS) not responding to the conventional therapies. Having the option of VV ECMO does not
mean that it is applicable to all cases in all circumstances. It is important to understand for an
ECMO specialist that there are several options available to manage a case of ARDS before we
even start thinking of this modality.
The initial measures to treat the cause of ARDS are as follows:
■ Sepsis, pancreatitis, trauma, shock, etc. to be managed early and appropriately
■ Restricted use of fluids and blood transfusions
■ Early antimicrobial use
■ Lung protective ventilation strategies to prevent ventilator-induced lung injury(VILI)
■ Appropriate use of sedation and paralysis—self-inflicted lung injury prevention
■ Recruitment maneuvers
■ Advanced mode of ventilator
■ Proning the patient.
232 Section 2  Extracorporeal Membrane Oxygenation

Due to several risks involved and complexity of the procedure, ECMO is considered
when all conventional therapies have been exhausted. An objective prediction score for early
identification of the patients who need to be transferred or considered for ECMO within 12
hours of initiation of ventilation was developed by Bohman et al. in 2016 and published in
Journal of Critical Care.

Indications
■ Primary or secondary hypoxic respiratory failure, ECLS
– Considered if risk of mortality is 50% or greater
– Indicated if risk of mortality is 80% or greater
■ 50% mortality risk: PaO2/FiO2 < 150 on FiO2 > 90% and/or Murray score 2–3, age-adjusted
oxygenation index (AOI) score 60, or by acute physiology of stroke score (APSS) score
■ 80% mortality risk: PaO2/FiO2 < 100 on FiO2 > 90% and/or Murray score 3–4, AOI >80 APSS 8.
Despite optimal care for 6 hours or less, the decision for ECMO should be taken within 1–2
days of onset for best outcomes.
■ Hypercarbia on mechanical ventilation with high inspiratory plateau airway pressure
(Pplat) (>30 cm H2O)
■ Severe bronchopleural fistula
■ Need for intubation in a patient on lung transplant list.
Several other conditions are also coming under the ambit of this modality as it progresses.
But whatever the disease condition, it should be reversible or one should have an exit strategy
in mind.

VENOARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION


In contrast to VV ECMO, for which the primary focus is gas exchange, VA ECMO allows for
blood to be drained from a central vein and returned to the arterial system. This allows for both
respiratory (to a certain extent) and circulatory supports. Here, the ECMO circulation bypasses
the heart and the lungs completely or partially and resulting into dual arterial or systemic
circulation; the net circulation is the mixture of native and ECMO circulation. VA ECMO
support decreases cardiac work and reduces cardiac oxygen consumption while providing
adequate systemic organ perfusion with oxygenated blood. Basically, a circulation in parallel
to the native circulation is made.

Indications
Any form of extracorporeal support aims at normalizing organ perfusion till the endogenous
system is not normalized or replaced. It means that the aim of any mechanical support should
act as a bridge to recovery of the organ or to its transplant or to a destination therapy like
ventricular assist devices (VADs) or even as a bridge to another bridge. It can also act as a bridge
to a diagnosis in cases, which present in life-threatening conditions with little time to find out
the cause. But a word of caution—not all diagnosis if made after ECMO has been initiated will
Chapter 28  Indications of Extracorporeal Membrane Oxygenation 233
be amenable to treatment or recovery. Exit strategies in such cases should be predefined and
preexplained to the family (and patient in rare cases) as ethical dilemmas are very common in
such cases. For example, a young patient is in emergency room (ER) in refractory arrest with no
family or records to tell you the cause. You may proceed with extracorporeal cardiopulmonary
resuscitation (eCPR) and tide over the crisis. Now the best case scenario can be massive
pulmonary thromboembolism, which is managed followed by recovery. Worst case is that
this embolism is a result of a terminal malignancy, which you might find out later with poor
recovery of the cardiogenic shock and no option of transplant/VAD. This is called as a “bridge
to nowhere” when the patient becomes stuck with no option to go further for transplantation,
VAD, or recovery. Moreover, occurrence of hypoxic ischemic encephalopathy and fear of a
vegetative state can complicate things.
Clear communication, exit strategies, and careful patient selection can be helpful but as
you do more cases, you will realize that you can never be too careful. The ultimate emotional
burden and drainage of vital resources can be daunting reality that the family and the medical
team will have to face.
With this as a background, major indications of VA ECMO are outlined below. As we gain
more knowledge, the indications are growing, but basic principles of reversibility and exit
strategies should never be forgotten. Few of the common indications are discussed later in this
chapter.
■ Cardiogenic shock: Severe cardiac failure due to any of the following causes —
– Acute coronary syndrome
– Cardiac dysrhythmic storm refractory to other measures
– Sepsis with profound cardiac depression
– Drug overdose/toxicity with profound cardiac depression
– Myocarditis
– Pulmonary embolism
– Isolated cardiac trauma
– Acute anaphylaxis.
■ Postcardiotomy—inability to wean from cardiopulmonary bypass after cardiac surgery
■ Postheart transplant—primary graft failure after heart or heart–lung transplantation
■ Chronic cardiomyopathy
– As a bridge to longer term VAD support
– Or as a bridge to decision
■ Periprocedural support for high risk percutaneous cardiac interventions
■ Bridge to transplant.

CONTRAINDICATIONS TO EXTRACORPOREAL MEMBRANE OXYGENATION


Sometimes contraindications become more important than indications to avoid a catch-22
situation.
234 Section 2  Extracorporeal Membrane Oxygenation

Cardiogenic Shock due to Coronary Event


The leading cause of death in myocardial infarction (MI) patients is cardiogenic shock, despite
all modern measures. Cardiogenic shock is the product of the vicious cycle of mismatch of
“Demand and Supply” and all measures are aimed at breaking this cycle. The target tissue is
the stunned and hibernated tissue rather than the dead one. Vasopressors, inotropes, intra-
aortic balloon pump (IABP), etc. have been used with some improvement in survival.
The IABP-SHOCK II trial has placed a question mark on the survival benefits of IABP. Below
are the criteria mentioned by F Formica et al. to diagnose cardiogenic shock.

Hemodynamic Criteria
■ Systolic blood pressure (SBP) below 90 mm Hg (or more than 30 mm Hg below basal in
hypertensive patients) for more than 30 min
■ Use of vasopressors and inotropes to keep SBP above 90 mm Hg
■ Cardiac index of less than 2.2 L/min/m2
■ Pulmonary artery occlusion presslure of above 15 mm Hg.

Signs of Tissue Hypoperfusion


■ Pale, cool and clammy peripheries
■ Prolonged capillary refill times
■ Altered sensorium
■ Oliguria/anuria (less than 0.5 mL/kg/h)
■ Signs of pulmonary congestion
■ Tachycardia
■ Lactic acidosis
■ Mixed venous saturation below 65%.
Mainstay of management remains revascularization, fluids, oxygenation, and
catecholamines amongst others and IABP (counter pulsation) still cannot be ignored. In case
all these are not able to reverse the shock progression (generally 4–6 hours timeline, earlier
in emergent cases; individualized to patient status), full mechanical support is considered.
ECMO has the advantage of biventricular support, concurrent oxygenation, quick institution
and less expensive than other supports like left ventricular assist devices (LVAD), etc. It will
augment the cardiac output, providing rest to the cardiac muscles, optimizing demand supply
gap, with maintenance of organ perfusion.

Refractory Cardiac Arrest


Extracorporeal membrane oxygenation for refractory cardiac arrest can be challenging, both
technically and ethically. Very strict patient selection can help in making the right choice
though you can never be 100% sure. The mortality and morbidity after sudden cardiac arrest is
still high despite several guidelines and multidisciplinary approach adoption. ECMO is another
promising approach and results are yet to be analyzed. Why ECMO is considered promising
is because of its ability to restore circulation and oxygenation before return of spontaneous
Chapter 28  Indications of Extracorporeal Membrane Oxygenation 235
circulation (ROSC), because of its ability to interrupt end-organ damage, because of its ability
to give rest to the heart and correct dysrhythmias, because of its ability in helping in post-ROSC
care in hypothermia, coronary revascularization, pulmonary thromboembolism, and so on.
Extracorporeal Life Support Organization (ELSO) guidelines state when to consider for
eCPR. Downtime or no-flow time is important. It is duration of cardiac arrest with low cardiac
output during a CPR. Witnessed arrest with immediate CPR initiation is an ideal condition.
Reversible conditions, if known, would be a perfect setting though not available always. Several
cutoffs have been proposed from 5 minutes to 30 minutes, some even up to 90 minutes. But
more important is surety of the quality of CPR in terms of perfusion and metabolic parameters.
Contraindications as above still apply but decision needs to be rapid. A bridge to nowhere
situation can be quite common.

Postcardiotomy Shock
This specific subset of patients has been documented as having a higher mortality even on
ECMO as compared to other cardiac indications. Patients with shock postcardiotomies,
despite inotropes and IABP can be considered for ECMO support. Some might not be weaned
from cardiopulmonary bypass (CPB) even and have to be shifted to ECMO. The bridge is to
recovery but alternatives might need consideration including transplant.
The surgeon does have the option of central ECMO as chest is already open, though he
may decide otherwise. Central ECMOs can support higher flows with low risk of Harlequin
syndrome and is more physiological. But open chest can be an invitation to infection and
surgical removal need sternotomy and closure. Aortic dissection and aortic clots are some
other issues to reckon with.

Myocarditis
Myocarditis can cause a frightening degree of fall in cardiac function but what makes it a
major indication after ischemic events is the almost complete recovery that can occur if
organ perfusion is supported by pharmacological and mechanical supports, ECMO being one
of them. Presentation can vary from shock to resistant dysrhythmias to even cardiac arrest.
Depending upon the cause, viral, pharmacological, toxic, genetic, etc., ECMO can be a bridge
to recovery, transplant, VAD, etc. Indications and contraindications and factors guiding central
vs peripheral largely remain the same.

High-risk Procedures
As the experience with ECMO increases and high-volume centers gain confidence, the
indications for ECMO are increasing. One attractive option is the use of ECMO support in
patients with very poor cardiac functions in whom cardiac or noncardiac procedures were put
on hold in favor of medical management due to the risk of cardiac events intraoperatively. It
is unlikely that these will be validated by controlled trials and current data is more opinion,
experience, and anecdotes-based. Few procedures are below:
■ Extracorporeal membrane oxygenation-assisted percutaneous coronary indications (PCI):
It can be elective in patients considered to be at high risk of intraoperative instabilities,
236 Section 2  Extracorporeal Membrane Oxygenation

e.g. very poor LV function, large areas of myocardium involvement, left main coronary
involvement, etc. Emergency ECMO-assisted PCI application in cardiac arrest or profound
shock on inotropes and IABP is a more common use.
■ Post-MI complications—interventions in conditions like free wall rupture, ventricular
septal defects (VSDs), and ventricular aneurysms.
■ Transcatheter aortic valve implantation (TAVI).
■ Other complex surgical procedures such as that performed on aorta, pulmonary
thromboembolectomy, and correction of congenital pediatric cardiac defects.

Septic Shock
Mortality reduction in sepsis has always been the target of many research and trials. With
occurrence of shock and oxygenation defects, it is but natural that ECMO might be considered
as an organ support modality. Data in pediatric populations has been more encouraging
than in adults. It is still seen as a modality with doubtful benefits primarily because it is a
hyperdynamic circulation, which is more than what a peripheral VA ECMO can support.
Moreover, in vasoplegic shock, it is the vessel, which is the problem, and ECMO cannot support
the vessels. However, when the cause of shock is a mix of different etiologies, whether ECMO
can help at that moment remains to be seen.
On basis of present literature, following support systems have been proposed:
■ Venoarterial extracorporeal membrane oxygenation—sepsis with cardiogenic shock as the
predominant component like in cardiac dysfunctions as part of sepsis or catecholamine
storm.
■ Venovenous extracorporeal membrane oxygenation—when ARDS is the predominant
component and shock might be contributed majorly by hypoxemia or high-pressure
ventilation.
■ Hybrid modes [veno-arterial-venous (VAV)] or central ECMO—when vasoplegia with
hyperdynamic circulation is predominant, the output can be matched by central ECMO.
In cases with mix of cardiac and pulmonary components, hybrid modes like VAV might be
considered.
Even as our selection processes become more objective and upfront, we might think that
our selection of patients will be more scientific and evidence based, the fact remains that
inherent human errors will still occur and we can never be too wrong. This cannot be more
emphasized in a country like ours when social and economic factors can be more forbearing.
Open communication and exit strategies might help in such cases.

SUGGESTED READING
1. Abrams DC, Prager K, Blinderman CD, et al. Ethical dilemmas encountered with the use of
extracorporeal membrane oxygenation in adults. Chest. 2014;145(4):876-82.
2. Bohman JK, Hyder JA, Pannu SR, et al. Early prediction of extracorporeal membrane oxygenation
eligibility for severe acute respiratory distress syndrome in adults. J Crit Care. 2016;33:125-31.
3. Brogan TV, Lequier L, Lorusso R, et al. Extracorporeal Life Support: The ELSO Red Book, 5th
edition. [online] Available from: https://www.elso.org/Publications/RedBook5thEdition.aspx.
[Last accessed October, 2019].
Chapter 28  Indications of Extracorporeal Membrane Oxygenation 237
4. ECMO Specialist Training Manual, 3rd edition. ELSO. [online] Available from: https://www.elso.
org/Home.aspx. [Last accessed October, 2019].
5. ELSO Guidelines for Adult Cardiac Failure. v1.3. [online] Available from: https://www.elso.org/
Resources/Guidelines.aspx. [Last accessed October, 2019].
6. ELSO Guidelines for ECPR Cases. v1.3. [online] Available from: https://www.elso.org/Resources/
Guidelines.aspx. [Last accessed October, 2019].
7. Extracorporeal Life Support Organization (ELSO). (2017). Guidelines for Adult Respiratory Failure.
[online] Available from: https://www.elso.org/Portals/0/ELSO%20Guidelines%20For%20Adult%
20Respiratory%20Failure%201_4.pdf. [Last accessed October, 2019].
8. Garan AR, Kirtane A, Takayama H. Redesigning care for patients with acute myocardial infarction
complicated by cardiogenic shock: the “Shock Team”. JAMA Surg. 2016;151(7):684-5.
9. Han JJ, Swain JD. The perfect ECMO candidate. J Am Coll Cardiol. 2018;71(10):1178-82.
10. Sangalli F, Patroniti N, Pesenti A. ECMO-Extracorporeal life Support in Adults. Germany: Springer;
2014. pp. 1-489.
11. Schmidt M, Burrell A, Roberts L, et al. Predicting survival after ECMO for refractory cardiogenic
shock: the survival after veno-arterial-ECMO (SAVE)-score. Eur Heart J. 2015;36(33):2246-56.
CHAPTER 29
Know the Extracorporeal Membrane
Oxygenation Machine: Circuit and Hardware
Vinod Kumar Singh

INTRODUCTION
Extracorporeal life support (ECLS) is the use of mechanical devices to temporarily (days to
months) support heart or lung function (partially or totally) during cardiopulmonary failure.
Extracorporeal membrane oxygenation (ECMO) is an extracorporeal life-support system,
which supports the function of the lungs, the heart, or both, typically applied when patients’
illnesses are refractory to other standard procedures. It is indicated in severe heart or lung
failure with 80% risk of mortality.
Modern ECMO is much safer, simpler, and reliable than the early ECMO equipment, and
patients could be managed for weeks, primarily by the bedside in ICU across a wide variety of
patient sizes from neonates to adults.
Components of a typical ECMO system are:
■ Extracorporeal membrane oxygenation circuit
■ Membrane oxygenator
■ Roller or centrifugal pump
■ Extracorporeal membrane oxygenation console
■ Vascular catheters
■ Oxygen blender
■ Heat exchanger.

EXTRACORPOREAL MEMBRANE OXYGENATION CIRCUIT


Extracorporeal membrane oxygenation circuit typically consists of a drainage cannula (venous
cannula), a centrifugal pump, a heat exchanger embedded in a membrane oxygenator and an
outflow cannula that transports arterialized blood. Circuits can vary from simple to complex
and may include a variety of blood flow and pressure monitors, continuous hemoglobin
saturation monitors, circuit access sites, and a bridge connecting the venous access and
arterial infusion limbs of the circuit (Figs. 1 to 3).
Chapter 29  Know the Extracorporeal Membrane Oxygenation Machine: Circuit and Hardware 239

Fig. 1: Extracorporeal membrane oxygenation (ECMO) system—circuit design.

Fig. 2: Venovenous extracorporeal membrane oxygenation (VV ECMO).


(IJV: internal jugular vein)

Figs. 3A and B: Percutaneous femoro-femoral VA ECMO.


(AC: arterial cannula; VC: venous cannula; RR: retrograde reperfusion; VA ECMO: venoarterial extracorporeal
membrane oxygenation)
240 Section 2  Extracorporeal Membrane Oxygenation

Circuit and Tubings


Circuit tubing used is made from a polyvinylchloride (PVC)-based plastic compound. ECMO
circuit needs to be functional and portable, yet ideally, one should attempt to limit the size
of the foreign surface of the circuit. This is because when blood is exposed to the nonbiologic
surfaces of the circuit, a complex biologic response is initiated involving both the coagulation
pathway and the inflammatory response pathway. The less complicated the circuit, easier it
will be to manage and the fewer the connectors and stopcocks, the less potential sites of flow
turbulence and blood stasis.
Circuit is coated with a biocompatible lining to reduce the systemic inflammatory response,
risk of thrombosis and bleeding, although no coating to date has been shown to eliminate
this reaction completely. Shorter tubing may also optimize venous drainage as there is less
resistance to blood flow.
Extracorporeal membrane oxygenation circuits usually have a variety of monitors including
an integrated blood pump flow monitor, which measures total circuit blood flow. A separate
ultrasonic flow detectors that can be placed on venous drainage and arterial infusion limbs
of the circuit. The best way to monitor ECMO circuits is without interrupting the blood path.
In most of the centrifugal pump, the flow sensor is located on the downstream side of the
pump. It is clamped over the circuit tubing going to the oxygenator. The flow sensors require a
conductive interface between the sensor and the circuit. This is usually a gel or paste.
Extracorporeal membrane oxygenation circuits can also include a bridge of circuit tubing
connecting the proximal venous access limb of the circuit to the proximal arterial infusion limb
of the circuit. This bridge is used to recirculate blood through the circuit if the patient needs to
be removed temporarily from support. It is also particularly useful in venoarterial (VA) support
during weaning of flow to low levels of support. The patient can be clamped off from the ECMO
circuit to determine if adequate gas exchange and hemodynamics can be maintained while
flow continues through the bridge (Fig. 4).

Pressure Monitors
Circuit pressures can be measured at three important locations within the ECMO circuit.
Venous access pressures measured before a centrifugal blood pump help ensure excessive

Fig. 4: Flow sensor.


Chapter 29  Know the Extracorporeal Membrane Oxygenation Machine: Circuit and Hardware 241
suction is avoided and help determine the adequacy of venous drainage and circuit volume.
Circuit pressures are also commonly measured before and after the gas exchange device, and
this is also where most centers have circuit access sites. If both pressures rise, this indicates
increased resistance to flow post-oxygenator and may be a result of obstruction to the inflow
cannula. An increase in the difference between the pre- and post-oxygenator (transmembrane)
pressures suggest an increase in the resistance inside the oxygenator.

PUMPS (FIG. 5)
The circuit flow is achieved using a pump, which is either centrifugal or a roller. Centrifugal
pumps are increasingly used rather than roller pumps. ECMO pump should be able to provide
a wide range of flows (75–200 mL/kg/min) without exerting excessive shear stress on red blood
cells thus causing hemolysis. Currently available ECMO pump technology can be categorized
into two major types—roller and centrifugal (Fig. 5).
Extracorporeal life support with roller head (semiocclusive) pump and a silicone
membrane lung has been a reliable system for years. However, for ECMO centrifugal pumps are
increasingly used rather than roller pumps. Centrifugal pumps are driven by electromagnetic
induction motors which generate a flow (described in terms of liters/minute), created by the
rotation of the cones, fins, or vanes and rotors. Flow depends on the speed of rotations per
minute (RPM) of the centrifugal pump, the hemodynamic conditions including the preload or
afterload, and the characteristics of the inflow or outflow cannula that are used including their
positioning. To ensure adequate preload, the centrifugal pump and the oxygenator should
preferably be below the level of the right atrium (RA) of the patient.
The important points about the ECMO pump are:
■ The rotation is set at a fixed rate, so the rate at which the blood travels through the pump is
continuous and nonpulsatile.
■ Rate at which the blood travels through the pump is called as the flow of the circuit.
■ The pump speed is in RPM.
■ Typical pump speeds are about 2,000–6,000 RPM.

Fig. 5: Schematic diagram of roller and centrifugal pumps.


242 Section 2  Extracorporeal Membrane Oxygenation

■ Pump speeds higher than 4,500 RPM are associated with significant hemolysis.
■ Flow through the pump depends on:
– Pump speed: Higher the speed, the more flow through the pump.
– The blood volume: This can be thought of as the “preload”—the more blood available to
the pump, higher the flows it can achieve.
– Downstream resistance: Also called “afterload”—the more resistance the pump faces,
the less flow the pump can achieve (Table 1).

PUMP CONSOLE (FIG. 6)


Pump console provides the controls for pump blood flow rate and speed. It has a battery
backup of 90 minutes. It can be incorporated into the bypass machine or stand-alone mode.

HEATER/COOLER MACHINE
A heater/cooler machine is attached to oxygenator to regulate patient temperature aim to
maintain normothermia.

OXYGENATOR (FIG. 7)
The purpose of oxygenator is to add O2 and remove CO2 from blood. It is placed distal to the
pump. Many different materials are used over the years including silicone rubber, polypropylene
hollow fiber devices, compressed surface polymethylpentene (PMP), polyvinylchloride,
polyurethane, etc.
Silicone rubber membrane lung has been the standard oxygenator used for ECMO
applications for a long time. It is constructed of a flat reinforced sheet of silicone rubber
membrane envelope wrapped around a wire mesh in a spiral coil. Flow of blood and gas occurs
in countercurrent directions within the silicone lung and gas exchange occurs by diffusion
across the membrane. It is very effective at exchanging O2 and CO2, a separate heat exchanger

Table 1: Hydrodynamic characteristics of ECMO pumps.


The peristaltic (roller) pumps The centrifugal pump
• Ability to set totally or partially occlusive • Nonocclusive
• Positive displacement—pushes blood by “squeezing” • Passive displacement—cones or impellers create
raceway kinetic energy using centrifugal force of fluid
• Automatically calculated blood flow constrained vortexing
(stroke volume × revolutions per minute) • Revolutions per minute are proportional to
• Blood flow is independent of resistance resistance
• Flow is inversely proportional to resistance
• Priming volume is low
• Blood flow rate 5–10 LPM
• Low surface area
• Low blood transit time
• No stagnant areas
(ECMO: extracorporeal membrane oxygenation)
Chapter 29  Know the Extracorporeal Membrane Oxygenation Machine: Circuit and Hardware 243

Fig. 6: ECMO console.


(RPM: rotations per minute; LPM: liters per minute)

Fig. 7: Quadrox ECMO oxygenator.

is required for small membrane lungs and this has a high resistance to flow, which limits the
maximum blood flow. Also it takes longer to prime and is much harder to de-air.
The newer hollow fiber PMP oxygenators are extremely efficient at gas exchange and
demonstrate minimal plasma leakage; have relatively low resistance to blood flow, making them
easy to prime; and are well suited for use with centrifugal blood pumps. PMP oxygenators are
more compact, optimize blood flow, and decrease the surface area of the membrane and heat
exchanger, thus reducing its potential for thrombus formation and inflammatory activation. The
low prime volume enables a center to utilize one device for all size of patients and these circuits
can be left assembled and crystalloid primed, with the benefit of support implementation within
minutes. The early experience with the PMP devices established them to be robust and long-
lasting, with limitation of the inflammatory response and decreased transfusion requirements,
making them well suited for long-term use. These new generation oxygenators also contain
an integrated heat exchange device, making it possible to precisely control body temperature
without the need for additional components.
A gas blender mixing air and O2 is connected to oxygenator permitting the adjustment of
exchange O2 and CO2 selectively.
244 Section 2  Extracorporeal Membrane Oxygenation

Especially, the flow of the gas mixture (“the sweep”) acts to determine the extraction of CO2
and the FiO2 from 21% to 100% (the oxygen concentration of the mixture) acts to govern the
transfer of oxygen into the blood.
The pressure drop generated in the oxygenator depends on its physical characteristics or by
variation of its internal resistance during ECMO use (including blood temperature, viscosity,
and thrombus formation on the membrane). It is measured by the pre- and post-oxygenator
pressure gradient (P2–P3). An increase in the pressure drop of the oxygenator may indicate
deterioration of the hemodynamics of the membrane, which in turn may impair gas transfers
and should prompt consideration regarding changing of the oxygenator (Figs. 8 and 9).

Fig. 8: Quadrox ECMO oxygenator side view.

Fig. 9: Extracorporeal membrane oygenator circuit.


Chapter 29  Know the Extracorporeal Membrane Oxygenation Machine: Circuit and Hardware 245
Oxygenation depends on:
■ The flow—higher flows allow more blood to be oxygenated.
■ The FiO2—increasing FiO2 achieves a higher partial pressure of oxygen.
■ The membrane integrity—if there is something present on the membrane (e.g. blood clots)
that impairs diffusion, oxygenation will decrease.
Carbon dioxide removal depends on:
■ The sweep—higher sweep speeds result in higher CO2 removal.
■ The flow—if the flow is increased without increasing the sweep, then CO2 removal can be
impeded.
■ The presence of water vapor in the membrane—this can impede CO2 removal.

VASCULAR CANNULAS
The blood flow in the ECMO circuit is determined by the size of the cannula (internal diameter
and length), the design, the pressure drop, and the positioning. Several types of cannulas
are currently available in a variety of sizes, with distinct features that may be used to adopt
a cannulation strategy that is customized to the unique requirements of individual patients.
Single lumen cannulas are used to provide venous and arterial access for patients receiving VA
ECMO or multiple site venous access for patients receiving VV extracorporeal support.
Most cannulas are manufactured from biocompatible polyurethane, which may be
coated with heparin or nonheparin polymers that may reduce platelet activation and the
inflammatory response at the blood–cannula interface. Cannulas are available in sizes ranging
from 6 Fr (2 mm diameter) to 51 Fr (17 mm diameter). Most cannulas are manufactured with
wire-reinforced bodies that are designed to prevent luminal occlusion. In general, the cannulas
have a radiopaque marker, though the distal few centimeters are often radiotransparent.
Overall cannula length and cross-sectional area, which impart an inherent resistance to
blood flow, must be considered during cannula selection to achieve optimal venous drainage.
Consequently, cannula selection should be based on the estimated level of support (flow rate)
to be provided and the size of the vessels to be accessed.
The access for ECMO must be large enough to support blood flow equivalent to patient’s
entire cardiac output, i.e. 5 L/min in an adult.
Venous cannulas (the inflow cannula) are longer than the outflow cannulas (±55 cm).
They have a larger diameter than outflow cannulas (15–29 Fr) and a larger proportion of their
length is multiperforated. These features reduce the pressure drop and limit the phenomena of
chattering, avoiding a significant collapse of the wall of the RA or the inferior vena cava (IVC).
Arterial cannulas (outflow cannula) are smaller than venous cannulas both in terms of
diameter (15–23 Fr) and overall length. They have some perforations at their distal tip, though
these are not as extensive as in the venous cannulas. According to their characteristics, a
pressure drop at the outflow cannula can be observed when P3 increases causing a decrease in
flow, despite a constant afterload and RPM of the centrifugal pump. During femoro-femoral VA
ECMO, the outflow cannula is placed into the common femoral artery. The particular position
of the cannula can cause ischemia of the ipsilateral lower limb. This can be prevented by the
introduction of a 6 Fr catheter for a distal perfusion connected to the Luer connector of the
outflow cannula and introduced few centimeters downstream the superficial femoral artery.
246 Section 2  Extracorporeal Membrane Oxygenation

A newer development is dual lumen cannulas [e.g. OriGen (Austin, TX) dual lumen
cannula; Covidien ECMO (Mansfield, MA) cannula; Avalon (Rancho Dominguez, CA) Bi-
Caval dual lumen cannula].
They provide venovenous support via a single jugular venous access site. Deoxygenated
blood is removed from the patient via one lumen and then returned to the patient via a smaller
lumen.
Echocardiographic or fluoroscopic imaging is necessary to verify proper cannula
placement. The Avalon cannula is available in sizes ranging from 13 Fr to 31 Fr, which enables
it to be used to support neonates through to adults (Fig. 10).
The key points about the drainage and return cannulas are:
■ Drainage cannulas are larger and typically 23–29 Fr.
■ The larger the cannula, the less resistance to flow it has.

B
Figs. 10A and B: Examples—(A) Access and (B) Return cannulas.
Chapter 29  Know the Extracorporeal Membrane Oxygenation Machine: Circuit and Hardware 247
■ The shorter the cannula, the less resistance to flow it has.
■ Drainage cannula is situated in large central veins, typically IVC, SVC, or the right atrium
(this is discussed further in the next section).
■ Depending on the configuration (see the next section), return cannula is situated either in
the right atrium or in the aorta.
■ The drainage cannula often has multiple orifices so they drain all along their length
(Figs. 11 to 13 and Table 2).

Fig. 11: Double lumen cannula.


Image source: Maquet.

Fig. 12: Echo-guided bi-caval dual lumen ECMO catheter insertion.


Image source: Maquet.
248 Section 2  Extracorporeal Membrane Oxygenation

Fig. 13: Extracorporeal membrane oxygenation (ECMO) disposables.

Table 2: Cannula sizes and flow.


Arterial
flow (mL/min) Size (Fr) External diameter (mm)
0–400 8 2.66
400–700 10 3.33
700–1200 12 4.00
1200–1700 14 4.66
1700–2000 15 5.00
2000–2500 17 5.66
2500–3500 19 6.33
3500-> 21 7.00
Venous
flow (mL/min) Size (Fr) External diameter (mm)
0–350 8 2.66
350–600 10 3.33
600–1000 12 4.00
1000–1400 14 4.66
750–1000 15 5.00
1000–1500 17 5.66
1500–200 19 6.33
2000–2500 21 7.00
2500–000 23 7.66
3000–3600 25 8.33
3600–4500 27 9.00
4500-> 29 9.66
Chapter 29  Know the Extracorporeal Membrane Oxygenation Machine: Circuit and Hardware 249

HEAT EXCHANGER (FIG. 14)


The oxygenator is connected to a heat exchanger, which allows the blood to be warmed as it
passed through the oxygenator.
■ Blood in the ECLS circuit is exposed to the ambient temperature so it must be warmed to
avoid heat loss.
■ The ECLS circuit has a heat exchanger, and when it is active, it warms the blood to 37°C.
■ If the patient is experiencing excessively high temperatures, the heat exchanger may be
turned off, and the blood will be passively cooled by the temperature of the room.

BLENDER
■ The blender is a device, which provides fresh gas to the oxygenator. The gas is a mixture of
nitrogen and oxygen.
■ The desired fraction of oxygen is programed and varies from 21% (room air) to 100%
(Fig. 15).

NOMENCLATURE
Before getting into specific configurations, it is important to understand how to describe ECLS
configurations using a common language. The Extracorporeal Life Support Organization
(ELSO) has developed a nomenclature for describing ECMO configurations. The following
description is adapted from the official treaty for Nomenclature in ECLS (Conrad et al.,
AJRCCM 2018).
■ All drainage cannulas are written on the left side of the hyphen, and return cannulas on
the right.
■ All cannulas contributing to the primary (major) draining and return circuit flow are
written in upper case letters.

Fig. 14: Heat exchanger.


250 Section 2  Extracorporeal Membrane Oxygenation

Fig. 15: Blender.

■ For example, “VV ECMO” would represent venous drainage and venous return for
venovenous support.
■ All cannulas with minor flow for secondary drainage, unloading of specific anatomical
location, or to promote distal perfusion are written in lowercase letters after the major flow
cannula to which side it belongs.
■ For example, “V-Aa” represents venous drainage, arterial return and secondary arterial
return such as for distal perfusion.
■ The use of a dual lumen cannula for venovenous support would be indicated with a
preceding “(dl)” abbreviation, e.g. “(dl) VV”.
■ The vessel that is cannulated is described using subscripted lowercase letters. Two common
examples include:
– The traditional two cannula venovenous configuration with drainage from the femoral
and return to the internal jugular would be indicated as “Vf-Vj”.
– Bifemoral cannulation for venoarterial support would be indicated as “Vf-Af”.

REFERENCES
1. Conrad SA, Broman LM, Taccone FS, et al. The Extracorporeal Life Support Organization Maastricht
Treaty for nomenclature in extracorporeal life support: a position paper of the Extracorporeal Life
Support Organization. Am J Respir Crit Care Med. 2018;198(4):447-51.
2. Byrnes JW, Fiser RT. Comparing outcomes in ECMO between roller and centrifugal pumps in the
face of evolving technology. Ann Thorac Surg. 2013;96(1):376.
3. Extracorporeal Life Support Organization (ELSO) General Guidelines for all ECLS Cases August,
2017.
CHAPTER 30
Cannulation, Priming and
Initiation of ECMO
Manender Kumar, Sarju Ralhan, Dinesh Garg

CANNULATION
Basic concept in cannulation of extracorporeal membrane oxygenation (ECMO) involves
insertion of two cannulas—access or drainage cannula and supply or returning cannula. In
case of venovenous extracorporeal membrane oxygenation (VV ECMO), access cannula
drains deoxygenated blood from the patient, and supply cannula returns oxygenated and
decarboxylated blood back to the right atrium. This configuration relies on patient’s own
circulation and requires adequate cardiac function. In case of venoarterial extracorporeal
membrane oxygenation (VA ECMO), access cannula drains deoxygenated blood from
the patient and returning cannula returns oxygenated and decarboxylated blood into the
patient’s arterial system, thus also providing circulatory support. In addition, some centers
are also employing triple cannulation strategies, which are the modifications of VV and VA
configurations.1
The insertion of cannula is most commonly performed by percutaneous approach—by
placing the cannula into the major vessels by using the Seldinger technique. This is a preferred
technique of cannula placement in adult and pediatric (>10 kg) patients. The major advantage
of this technique is that it can be done bedside and ligation of vessels is avoided and bleeding
complications are reduced. This cannulation can be done with the help of ultrasound or
fluoroscopy. Ultrasound will help in sizing of vessels, localization of vessels, and confirmation
of position; and fluoroscopy will help in inserting guidewire and cannula placement. X-ray
also helps to access the appropriate position of cannula. The percutaneous approach may also
be combined with surgical cutdown, i.e. first exposing the vessel by surgical cutdown and then
inserting the cannulas by Seldinger technique.

Cannula Size and Selection


The selection of the cannula plays a very important role during ECMO to provide adequate flow
to the patient with limited pressure drop. Various types of single- and double-lumen cannulas
are available in the market. These cannulas are wired reinforced to prevent kinking. Arterial
cannula has single opening and the venous cannula has multiple openings are available in
252 Section 2  Extracorporeal Membrane Oxygenation

Fig. 1: Wire reinforced cannulas: (A) Multiport venous cannula; (B) Arterial cannula.

various length and sizes (Fig. 1). Thin-walled cannulas are preferred, as they present lower
resistance to flow because of their large effective internal diameter. The size of the arterial
cannula is selected so that it can maintain flows to achieve a cardiac index of 2.0–2.4 L/min/m2
with minimum resistance to the blood flow and venous cannula should be used, which gives
good drainage at the 20 mm Hg of pressure drop. The size of the cannula is decided by desired
flow and the size of the vessels.

As per Poiseuille’s equation: Flow α Radius4 × pressure/Length


Thus, the largest size cannula with minimum length should be selected to maximize the
flow through the cannula. The vessel diameter can be assessed by ultrasonography and the
size of the cannula can approximately be calculated by following formula:

Calculated circumference = π × D (π = 3.14)


It is important that the cannula size is smaller than the maximum size of the vessel in order
to allow some amount of blood to pass around the cannula, which prevents complications like
edema, stasis, venous hypertension, deep vein thrombosis (DVT), ischemic injury, and limb
ischemia. Generally, about 25–30 Fr multistage cannulas are used for venous drainage and
15 Fr, 17 Fr, and 19 Fr cannulas are used as supply cannulas.

CANNULATION SITES
Venovenous Extracorporeal Membrane Oxygenation
The usual sites employed in VV ECMO are the femoral vein for the insertion of drainage
cannula and right internal jugular vein for the insertion of supply cannula (Fig. 2). Large-
bore cannulas of about 25–30 Fr size are inserted into the femoral vein for drainage and
smaller cannulas of about 19–23 Fr are usually sufficient for the supply of blood into the right
internal jugular vein. The cannulas should be positioned using fluoroscopy or echocardio-
graphy and the tips of cannulas should be at the level of junction of right atrium with inferior and
superior venae cavae, respectively. An important point to take into consideration is that there
should be a gap of around 7–8 cm between the tips of these cannulas; otherwise the oxygenated
blood may get drained back into the drainage cannula, a phenomenon known as “recirculation”.
The right and left femoral veins can also be used for insertion of drainage and supply
cannulas (Fig. 3). This technique is not frequently employed as there is a higher risk of
recirculation and risk of stasis of blood in inferior vena cava.
Chapter 30  Cannulation, Priming and Initiation of ECMO 253

Fig. 2: Venovenous extracorporeal membrane oxygenation: Drainage cannula in femoral vein and supply cannula
in right internal jugular vein (RIJV).

Fig. 3: Venovenous extracorporeal membrane oxygenation: Both drainage and supply cannulas in femoral veins.

The alternative way of establishing access in VV ECMO is placing a double-lumen bicaval


cannula through right internal jugular vein (Fig. 4). It has three ports. The proximal port drains
blood from superior vena cava and the distal port drains blood from the inferior vena cava.
The middle port lies in the right atrium and faces tricuspid valve and is used to supply the
oxygenated blood. The placement of this cannula requires fluoroscopic or echocardiography
guidance. The main advantage of this cannula is reduced risk of bleeding and lesser chances
of recirculation. As this technique involves only upper body access, the patient can be easily
254 Section 2  Extracorporeal Membrane Oxygenation

Fig. 4: Double-lumen bicaval cannula through right internal jugular vein.

mobilized and weaned off from ventilatory support thus facilitating “awake ECMO”. The
disadvantages are the risk of right atrial or ventricular perforation, limited flow rates and
increased incidence of hemolysis on higher flow rates with currently available cannulas.2,3

Venoarterial Extracorporeal Membrane Oxygenation


Peripheral cannulation is the most commonly employed technique for VA ECMO. The venous
cannulation is commonly performed via femoral vein. The alternative site for peripheral
venous cannulation is through right internal jugular vein. Regardless of the site, tip of the
venous cannula should be positioned in mid-right atrium that ensures good venous return
from both superior and inferior venae cavae. The most common site used for arterial
cannulation is femoral artery (Fig. 5). Due to its ease of access, it can also be used during
cardiopulmonary resuscitation for extracorporeal cardiopulmonary resuscitation (eCPR).
In general, the contralateral side is used when femoral vein is used for venous drainage.
The tip of the femoral arterial cannula should lie in the common iliac artery. The alternative
site for arterial cannulation is axillary or subclavian artery (Fig. 6). This technique requires
direct exposure of the artery and putting the 8 mm side graft over the artery. Such upper body
cannulation using subclavian artery with right internal jugular vein allows for “awake ECMO”,
thus allowing early mobilization and active physical therapy.
The major concerns associated with peripheral femoral arterial cannulation are left
ventricular (LV) distension and the “watershed phenomenon”. The left ventricle in cases of
VA ECMO is not fully unloaded by venous drainage as it receives blood from the other sources
such as bronchial and Thebesian veins that bypass the venous drainage circuit. As the blood
flow through the arterial cannula is pumped in a retrograde manner, it creates significant
afterload to the already compromised and diseased left ventricle. This in addition to conditions
having incompetency of aortic valve, can lead to significant LV distension, thus leading to
increased end diastolic pressures, reduced coronary artery perfusion, and pulmonary edema.
Chapter 30  Cannulation, Priming and Initiation of ECMO 255

Fig. 5: Venoarterial extracorporeal membrane oxygenation. Drainage cannula in femoral vein and supply cannula
in femoral artery.

Fig. 6: Venoarterial extracorporeal membrane oxygenation. Drainage cannula in right internal jugular vein (RIJV)
and supply cannula in axillary/subclavian artery.

This condition can be minimized by optimal positioning of venous drainage cannula to


maximize blood drainage, fluid offloading by using diuretics or continuous venovenous
hemofiltration (CVVH), optimizing inotropic and vasopressor therapy for reducing afterload
and increasing myocardial contractility, adjusting ECMO flows, balloon atrial septostomy,
direct venting of LV by apical or transatrial routes or insertion of mechanical devices such as
Impella or Tandem Heart to offload left ventricle and left atrium, respectively.
256 Section 2  Extracorporeal Membrane Oxygenation

Another effect of retrograde flow through arterial cannula is the “Watershed Phenomenon”
or “North South syndrome” or “Harlequin syndrome”. It typically occurs due to the competition
of flow between the LV ejection flow and the retrograde ECMO flow, creating a “watershed
point”. This typically occurs between the ascending aorta and renal arteries, but its position
depends upon the LV output and the ECMO flow. As per this result, the body parts receiving
blood supply proximal to the watershed point, mostly coronary arteries and first branch from
aortic arch, get blood from LV output and those receiving blood distal to the watershed point
are dependent on ECMO flow. Whereas the blood returning through ECMO arterial cannula
is enriched with oxygen, this may not be the case for blood ejected through left ventricle
as oxygenation of this fraction of blood depends on the underlying lung condition such as
pneumonia, acute respiratory distress syndrome (ARDS), pulmonary edema, etc. Thus, there
may exist differential hypoxia in the body parts being supplied by LV blood, despite good
perfusion pressures. This is particularly of concern for perfusion of coronary arteries and
cerebral arteries as the resultant hypoxia may have deleterious effects on these vital organ
systems. Therefore, cannulation of right upper extremity artery, preferably right radial artery
is warranted to monitor the oxygenation of heart and brain. This condition can be managed
by adjusting ventilatory settings and optimization of lung function or upgrading to triple
cannulation as discussed further.4,5
The cannulation of femoral artery may also lead to distal limb ischemia. This may be due
to partial or complete occlusion of the vessel. Also, the retrograde flow through the arterial
cannula also directs the remaining little native blood to flow in the retrograde direction. This
condition can be managed by careful monitoring of limb perfusion by Doppler. An antegrade
5 Fr cannula can be inserted into the femoral artery prior to the insertion of femoral arterial
supply cannula and can be connected to the supply circuit. Alternatively, tibial artery can also
be cannulated for distal perfusion.
The problem with axillary or subclavian artery cannulation may be distal limb hyperemia.
It can lead to compartment syndrome and may require fasciotomy. This technique is more
invasive and there is also a higher risk of injury to the vessels and nerves of the arm.

Central Venoarterial Extracorporeal Membrane Oxygenation


Central VA ECMO involves the cannulation of right atrium and ascending aorta under direct
surgical exposure. This is an invasive procedure and can be done through sternotomy or right
anterior thoracotomy. This technique is mainly employed as the extension of cardiopulmonary
bypass in open heart surgeries or when the peripheral VA cannulation is not sufficient to
provide adequate perfusion pressures or oxygenation. The chest can be left open with the
sterile surgical dressing to cover the chest or the cannulas can be tunneled through the soft
tissue and skin, and the chest can be closed. The major advantage of this technique is very good
venous drainage with excellent antegrade flow delivery into the arterial system, thus offsetting
the watershed phenomenon. LV distension is also not a problem, as LV can be emptied by
putting LV vent through LV apex or through the pulmonary veins. The disadvantages are major
risk of bleeding and infection and this technique needs cardiac surgical team expertise and is
difficult to institute during emergency.
Chapter 30  Cannulation, Priming and Initiation of ECMO 257

Triple Cannulation
It should be kept in mind that the physiology and requirement of the patient hemodynamics
keep on changing whichever type of ECMO had been instituted. To overcome the problems
encountered during VA or VV ECMO, triple cannulation with insertion of an additional
cannula is instituted as an upgrade of the existing VA or VV ECMO. It can be employed either
as VVA or VAV ECMO.
Veno-venous-arterial extracorporeal membrane oxygenation (VVA ECMO) is a variant of
VA ECMO, in which an additional venous cannula is inserted to improve the venous drainage
(Fig. 7). The venous drainage may be insufficient in case of smaller cannula diameter or in very
large patients that can lead to reduced ECMO flows or differential hypoxia as described above.
LV distension during VA ECMO is also an indication to improve the venous drainage to unload
the left ventricle. When upgrading VA ECMO, the additional venous cannula should always
be inserted under live imaging. A Y-connector is used to merge the flow from both venous
cannulas to a single tubing.
Veno-arterial-venous extracorporeal membrane oxygenation (VAV ECMO) is used in cases
of coexistent severe lung and heart failure. In this case, the venous drainage is through a single
venous cannula and the arterial flow is divided into two parts—one toward right atrium and
one toward the arterial circulation (Fig. 8). VAV ECMO provides simultaneous respiratory and
circulatory support. This is instituted either when lung failure develops during VA ECMO as
in cases of pneumonia, ARDS, pulmonary edema, etc. or when heart failure develops during
VV ECMO due to septic cardiomyopathy or myocarditis leading to decreased cardiac output.
In former case, the third cannula supplies oxygenated blood to the patient’s lungs and in the

Fig. 7: Veno-venous-arterial extracorporeal membrane oxygenation. Drainage cannula in femoral vein and supply
cannula in femoral artery. Additional venous cannula in subclavian/right internal jugular vein.
258 Section 2  Extracorporeal Membrane Oxygenation

Fig. 8: Veno-arterial-venous extracorporeal membrane oxygenation. Drainage cannula in femoral vein and supply
cannula in femoral artery with additional supply cannula in right internal jugular vein (RIJV).

latter case, the oxygenated blood is pumped into the arterial circulation by the third cannula.
The arterial outflow is diverted by using a Y-connector and balanced by adjustable clamps and
flow is monitored by flow sensors.

Complications of Cannulation
Utmost care should be taken during insertion of cannulas. At least 1% of the patients
may develop perforation of large vessels or even cardiac chambers. The other important
complications are listed below:
■ Cardiac arrhythmias
■ Laceration of vascular structure
■ Hemorrhage, including occult, such as retroperitoneal hematoma, hemothorax, and
pericardial
■ Air embolism
■ Inadvertent cannulation of smaller vessels, such as azygos, innominate or hepatic veins
■ Cavitation (bubbles trapped on the cannula wall being released in blood)
■ Blood trauma, including hemolysis
■ Compression of other structures (e.g. a venous cannula compressing an artery)
■ Pneumothorax
■ Infection.

Procedure
Strict sterility is to be maintained during cannulation. Administer heparin 150–200 IU/kg
and ensure ACT >250 seconds. The cannulas are then inserted under fluoroscopic or
echocardiographic guidance. Secure the cannulas by applying additional sutures and cover
the sites with transparent sterile dressings.
Chapter 30  Cannulation, Priming and Initiation of ECMO 259

PRIMING OF EXTRACORPOREAL MEMBRANE OXYGENATION CIRCUIT


A very important aspect of ECMO is circuit preparation and priming. This is done by the
perfusionist. Circuit priming should be done as fast as possible and strict asepsis has to be
maintained. Before starting, the priming volume of the circuit should be calculated according
to body surface area (BSA) and body mass index (BMI), so that we should know how much
volume we are going to add in patient’s circulation. The main purpose of priming is to de-air the
circuit by replacing the circuit air with the fluid. Priming can be done either with a crystalloid
or blood. The nature of priming fluid depends upon the age and weight of the patient, baseline
hemoglobin level, clinical situation, i.e. whether it is an emergency or an elective ECMO and
whether it is a VA or a VV ECMO. Once the circuit has been primed, it is kept in sterile condition
and can even be kept in this ready state for about 30 days.
Types of priming:
■ Crystalloid priming
■ Blood priming.

Crystalloid Priming
Any type of ECMO circuit is always primed with crystalloid solution first. This is done to de-
air the whole extracorporeal circuit. We can add other additives as demanded by the patient’s
biochemical parameters. Clear crystalloid prime with or without albumin is generally preferred
in adults and children above 30 kg. Many centers use CO2 to displace any nitrogen, which can
form bubbles. The major drawback of crystalloid priming is hemodilution and hypotension at
the start of ECMO. After priming, the heater unit is activated to bring the priming solution to
37°C to avoid the cold shock.

Blood Priming
Priming of ECMO circuit with allogeneic blood is done to prevent hemodilution. It is generally
preferred in newborns or small children and is used in case of adults only if hematocrit is low
(less than 25%).
In case of blood priming also, ECMO circuit is first primed with crystalloid solution and
then crystalloid solution is replaced by blood slowly. In newborn infants, one unit of adult
packed cells is enough to displace crystalloid solution. VV ECMO requires higher hematocrit
than VA ECMO.
Blood priming is generally preferred with fresh leukocyte-depleted blood (not more than
5 days old) so as to minimize the inflammatory response during onset of ECMO. If packed
RBCs are used, albumin is also added along with heparin and calcium gluconate. If fresh blood
is not available, then sodium bicarbonate is added to counteract the lactic acidosis of stored
blood.
Ionized calcium levels of 1.0 mEq/L are to be maintained in prime volume to avoid
myocardial depression and cardiac arrest that may happen at the initiation of extracorporeal
life support. 1 mg of calcium gluconate is added for each mL of blood prime. Calcium gluconate
is added only after the heparin has circulated for at least 5 minutes in ECMO circuit.6
260 Section 2  Extracorporeal Membrane Oxygenation

After circulating the blood prime, a gas priming is also done in the ECMO circuit. The gas
priming is done with 100% oxygen. The most commonly used method of gas prime is to turn on
the sweep gas flow with a FiO2 of 100% at 5 L/min for 2–3 minutes. After this, the gas is removed
from the oxygenator and a circuit gas analysis is done to measure the resulting pO2 and pCO2.
The target values in blood primed solution should be—sodium 136 mEq/L, potassium
3.5–6 mEq/L, total protein of 4 g/dL, albumin concentration around 3 g/dL, osmolarity of
about 280 mOsm/L ,and hematocrit of 45–55%.

Circuit Priming with Other Additives


Priming with albumin is done to decrease fibrinogen adsorption during initial blood contact.
This will reduce the inflammatory response and prevent any further drop in serum protein
level.
Sometimes priming with FFP is recommended in children for ECMO support after cardiac
surgery to prevent any further dilution of coagulation factors and antithrombin III.

Procedure (Fig. 9)
■ Connect the console to main power supply.
■ Take the Bioline circuit and flush it with CO2 @ 5 L/min for 3–5 minutes.

Fig. 9: Extracorporeal membrane oxygenation circuit diagram showing its components.


Chapter 30  Cannulation, Priming and Initiation of ECMO 261
■ Add heparin 3 IU/mL to the 1 L crystalloid solution such as Plasma-Lyte A and connect it
to the prime inlet port of the circuit.
■ Apply clamps at inlet and outlet tubing ends of the membrane.
■ Open the crystalloid solution bag and allow the circuit to fill by gravity. Gently tap the cone
to assist in de-airing.
■ Apply the ultrasonic contact cream at both sides of the flow sensor around the outlet of
centrifugal pump.
■ Fit the cone into the centrifugal pump head and lock the pump assembly unit.
■ Remove the pre-membranous clamp and let the membrane oxygenator de-air by gravity.
■ Remove pre- and post-membrane clamps and run the centrifugal pump to about 500 RPM
and circulate the priming solution for 3–5 min to de-air the circuit completely.
■ Calibrate the flow sensor—reduce the flows to about 0.5 L/min and clamp downstream the
centrifugal pump to prevent reverse flow. Reduce the pump speed to zero and wait until
the Rotaflow has stopped completely. Press “zero” button for about 3 seconds to calibrate
flow measurement to zero.
■ Attach heater/cooler unit.
■ Attach the pressure monitoring lines and zero all the transducers.
■ Connect gas blender to the oxygenator. The gas outlet line should always remain open.
■ Hand over the arteriovenous loop (AV loop) of the circuit to the surgeon.
■ Stop the pump. Clamp the AV loop and divide the lines.
■ Connect the drainage cannula to the access line and supply cannula to the supply line of
the circuit.

INITIATION OF EXTRACORPOREAL MEMBRANE OXYGENATION


Once cannulation is complete and the cannulas are connected to the circuit, before the
initiation of ECMO, we must follow a safety checklist to help minimize the errors and safety
risks. It is advisable to have a printed copy of the checklist while performing sign out for the
procedure. This checklist involves detailed reinspection of patient’s condition and equipment.

Initiation Procedure
After all the boxes in check list are ticked, ensure activated clotting time (ACT) >250 seconds.
Turn on the pump and increase the pump speed to about 500 RPM to provide forward flow and
open the clamps. The clamp from venous drainage line is opened and pump speed is gradually
increased to 1,500 RPM. Then clamp from blood outflow line is removed and pump speed is
further increased. The sweep gas flow should be started usually at 5–6 L/min keeping gas flow to
blood flow ratio as 1:1. Monitor the gas inlet pressure. The ideal gas pressure is about 40–45 psi.
In case of VA ECMO, pump speed is gradually increased to achieve the target blood flow
to maintain cardiac index of 2.0–2.4 L/min/m2. During this period, there may occur decrease
in venous drainage that may result in hypotension. Other causes of decreased venous return
such as cannula malpositioning should be excluded. Administration of blood products such as
packed red blood cells, albumin, or crystalloids should be considered. Fluid boluses should be
given as aliquots of 5–10 mL/kg and care must be taken to avoid fluid overload.
262 Section 2  Extracorporeal Membrane Oxygenation

ECMO INITIATION SAFETY CHECKLIST


■ Reconfirm written and informed consent
■ Patient’s name, hospital ID
■ Recording of patient’s height, weight, body surface area
■ Assessment of patient’s condition and anticipated problems
■ Plan of ECMO: VA ECMO or VV ECMO
■ Recording of vital signs including heart rate and rhythm,
arterial blood pressure, central venous pressure, rectal temperature
■ Recording of patient’s ventilator settings
■ Detailed neurological assessment of the patient including GCS,
pupillary size and reaction, any focal neurological deficit
■ Current ongoing infusions (inotropes, vasopressors, etc.),
IV fluids, nasogastric/orogastric feeds, sedation, etc.
■ Pre-ECMO investigations: Arterial blood gas, venous or mixed blood gas,
complete blood count, renal function test, liver function test,
blood lactate level, random blood sugar, blood grouping and
cross matching, prothrombin time, activated partial thromboplastin time,
activated clotting time (ACT), chest X-ray, echocardiography
■ Ensure availability of blood products
■ Check patency of IV access
■ Urinary catheter should be inserted
■ Emergency crash cart including defibrillator must be present at patient’s bedside
■ Reconfirm position of ECMO cannulas by transthoracic or
transesophageal echocardiography and check whether these are
properly secured and dressing is in place
■ Look for any signs of infection, bleeding, or hematoma at the cannulation site
■ Watch for all peripheral pulses in the limbs where cannulas have been placed
■ Tube clamps must be available at the bedside
■ Observe complete length of circuit tubing for any cracks or fibrin clot formation
■ Observe oxygenator for any clots, fibrin formation, or air accumulation
■ Ensure that all the connections are tight
■ Pump should be properly fitted in the cradle. Emergency hand crank should be
available. Watch out for any chatter in the pump
■ Check for display of RPM indicator
■ Flow sensor should be attached and lubricated
■ Zero the pressure transducers
■ Verify the functioning of heater and check the set water temperature
■ Verify gas supply and presence of reserve oxygen cylinder
■ Watch for setting of blender for sweep gas flow rate and FiO2
■ Watch out for pre-/postoxygenator pressures
Chapter 30  Cannulation, Priming and Initiation of ECMO 263
Similarly, in case of VV ECMO, pump flow is slowly increased to achieve target blood flow
and arterial oxygen saturation of >80%. As there are more chances of hypotension during
initiation of VV ECMO due to the “washout effect” and limited ability of VV ECMO to support
hemodynamics, inotropic support may be increased and care should be taken to maintain
normal calcium and potassium levels in circuit fluid. Another important parameter to be taken
care of during VV ECMO is “recirculation”. It means that a fraction of oxygenated blood flows
directly from reinfusion site to the venous drainage catheter and thus it does not go back to the
patient, resulting in decrease in arterial oxygen saturation of the patient. The bright red color
in the venous drainage cannula and tubing suggests recirculation. The fraction of recirculation
blood may also be calculated by following formula:

Recirculation fraction = {SvO2 (pre-oxygenator) − SvO2 (patient)}/


{(SvO2 (post-oxygenator) − SvO2 (patient)}
In this case, the cannula position may need to be readjusted and pump flows may have to
be increased to reduce recirculating fraction.
As there is limited ability of VV ECMO to achieve similar level of oxygen delivery as VA ECMO,
the oxygen content of the blood may be increased by packed red blood cell administration but
again keeping in mind that fluid overload has to be avoided.
Once the ECMO has been initiated, the ventilator settings should be minimized to give rest
to the lungs, whether it is VA ECMO or VV ECMO. The inotropic support may be decreased or
discontinued as tolerated by the patient.
Thus, in nutshell, for VV ECMO, the target flows must provide adequate arterial oxygenation
and for VA ECMO, the target flows must provide target mean arterial blood pressure and
adequate oxygen delivery to the patient.

ACKNOWLEDGMENT
The authors like to thank Mr Akshay Katoch, Perfusionist, Hero DMC Heart Institute, Ludhiana,
for his valuable contribution in writing this chapter.

REFERENCES
1. Extracorporeal Life Support Organization. ELSO guidelines for gardiopulmonary extracorporeal life
support. Version 1.4, Ann Arbor, MI, USA. [online]. Available from: www.elso.org. [Last accessed
October, 2019].
2. Pavlushkov E, Berman M, Valchanov K. Cannulation techniques for extracorporeal life support.
Ann Trans Med. 2017;5(4):70.
3. Napp LC, Kühn C, Hoeper MM, et al. Cannulation strategies for percutaneous extracorporeal
membrane oxygenation in adults. Clin Res Cardiol. 2016;105(4):283-96.
4. Lindholm JA. Cannulation for veno-venous extracorporeal membrane oxygenation. J Thorac Dis.
2018;10(Suppl 5):S606-12.
5. Jayaraman AL, Cormican D, Shah P, et al. Cannulation strategies in adult veno-arterial and veno-
venous extracorporeal membrane oxygenation: techniques, limitations and special considerations.
Ann Card Anaesth. 2017;20(Suppl):S11-8.
6. Kapoor PM. Manual of Extracorporeal Membrane Oxygenation (ECMO) in the ICU, 1st edition.
New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2013. pp. 1-392.
CHAPTER 31
Anticoagulation during Extracorporeal
Membrane Oxygenation
Srinivas Samavedam, Rajyalakshmi B

INTRODUCTION
Extracorporeal membrane oxygenation (ECMO) has become quite widespread in India since
the H1N1 pandemic of 2009. The indications for ECMO are varied including respiratory failure,
cardiogenic shock, and during cardiopulmonary resuscitation (CPR). Depending on the
indication, ECMO may be offered by the venovenous or the venoarterial route.
As the name implies, extracorporeal circulation is integral to ECMO and anticoagulation
becomes a necessity. Delivering and monitoring such anticoagulation is a major aspect of
running an ECMO service.

HEMOSTATIC DERANGEMENTS DURING EXTRACORPOREAL


MEMBRANE OXYGENATION
Hemostatic mechanisms can be disrupted during ECMO due to the following reasons:
■ The extracorporeal circuit can activate both coagulation and inflammatory pathways,
being a nonbiological entity.1
■ Intrinsic disease, such as pneumonia, viral myocarditis, or cardiac arrest, can also trigger
immune dysfunction and endothelial dysfunction.

EFFECTS ON PLATELETS
■ The high shear stress and turbulence in the ECMO circuit activate the platelets (Fig. 1).2
■ The platelets so activated adhere both to the circuit and to the damaged endothelium. This
sets in motion a consumptive coagulopathy associated with thrombosis.
■ The sequence initiated by thrombosis also facilitates adsorption of fibrinogen on to the
artificial circuit surface, which adds to platelet activation through glycoprotein IIb/IIIa
binding.
■ A true thrombocytopenia is expected because of the above-mentioned reasons. In
addition, thrombasthenia is also known to occur as a result of the turbulence as well as due
to metabolic derangements associated with underlying disease.
Chapter 31  Anticoagulation during Extracorporeal Membrane Oxygenation 265
■ The high shear stress during an ECMO run causes loss of high molecular weight multimers
of von Willebrand factors. This deficiency results in poor binding of the factor to platelets
and to the subendothelial matrix.
■ Severe qualitative platelet dysfunction for adenosine diphosphate (ADP)- and arachidonic
acid (AA)-mediated aggregation was found on thromboelastography-platelet mapping
studies.

EFFECTS ON COAGULATION SYSTEM


■ The exposure of the circulating factor XII and prekallikrein to the circuit activates them by
contact, triggering a downstream release of bradykinin, facilitating fibrinolysis.
■ The damage to the endothelium exposes the negatively charged collagen, which in turn
activates molecular weight kininogen, prekallikrein, and factor XII which form a complex
on collagen amplifying the intrinsic pathway.
■ Exposure of the subendothelial tissue factor of the damaged endothelium activated the
so-called extrinsic pathway through circulating factor VII. This is the major pathway
responsible for thrombosis and disseminated intravascular coagulation.
■ Enhanced consumption and decreased synthesis lead to acquired antithrombin (AT)
deficiency during ECMO predisposing to heparin resistance and thrombosis.

ANTICOAGULANT AGENTS
Unfractionated Heparin
The advantages of unfractionated heparin (UFH) are its cost, familiarity, and an age-related,
dose-dependent short half-life (range 1–2 hours).

Fig. 1: Schematic diagram of hemostatic impairement while patient on ECMO.


266 Section 2  Extracorporeal Membrane Oxygenation

Mechanism of Action
The effect of UFH is mediated via potentiation of the anticoagulant action of AT and induction
of the tissue factor pathway inhibitor, and results in inhibition of free thrombin, factors XIa, Xa,
IXa, and the tissue factor/factor VIIa complex.

Administration
Initial bolus: The usual dose is 50–100 units per kg body weight at the time of cannulation.
The bolus dose can be adjusted based on clinical factors such as:
■ Evidence of preexisting bleeding
■ Recent surgery or cardiopulmonary bypass
■ Pretreatment with protamine.
Infusion:
■ Therapeutic anticoagulation, classically defined by the activated clotting time (ACT) range
of 180–220 seconds, is usually achieved with infusion rates of 20–50 units/kg/hr.
■ The administration of platelets, increased urine output, or use of renal replacement therapy
may result in an increased UH requirement to maintain goal ACTs.
Limitations:
■ Ineffective inhibition of platelet-bound factor Xa, phospholipid-bound factor Va–Xa
complex, and fibrin-bound thrombin
■ Heparin-induced thrombocytopenia (HIT)
■ Heparin resistance:
– Heparin binds to plasma proteins including acute-phase reactants leading to heparin
resistance, especially in acutely ill patients.
– Heparin therapy itself produces a decrease in circulating AT which also leads to heparin
resistance.

ROLE OF ANTITHROMBIN III REPLACEMENT


■ Antithrombin is produced by the liver and is a natural inhibitor of all serine proteases
(except for factor VIIa and protein C), and the majority of its anticoagulant effect results
from inhibition of thrombin and factor Xa.
■ The optimal AT activity for any patient receiving UFH anticoagulation for extracorporeal
life support (ECLS) is unknown.3
■ Acquired AT deficiency may be a contributing factor to the patient’s heparin resistance. If
low AT activity levels are confirmed, AT replacement may be considered.
■ Some centers routinely administer AT replacement for AT activities <30-80%, while
others will treat low AT activity only if there is evidence of reduced UFH effect clinically
or based on low ACT, low anti-Xa levels, or minimal UFH effect on kaolin and heparinase
thromboelastogram (TEG) samples.
■ Of the ECLS programs that routinely replace AT as part of their anticoagulation protocol,
without consideration of other tests of UFH effect, most target levels range from >50% to
>100%.
Chapter 31  Anticoagulation during Extracorporeal Membrane Oxygenation 267

ALTERNATIVE ANTICOAGULANT AGENTS


Low Molecular Weight Heparin
■ Low molecular weight heparin (LMWH) can also be used.
■ Dose 1 mg/kg 12th hourly subcutaneously.
■ Efficacy can be monitored by checking anti-factor Xa levels, the target being 0.6-1 IU/mL.
■ The incidence of HIT is less common with LMWH.

Direct Thrombin Inhibitors4


■ Argatroban
■ Bivalirudin
■ Lepirudin.

Advantages
■ Unlike UH, the direct thrombin inhibitors (DTIs) are not dependent on AT for their
anticoagulant effect but directly inhibit both free circulating and fibrin-bound thrombin.
So, they are more reliable in patients with low or fluctuating AT activity.
■ Since DTIs do not bind to other plasma proteins or cells, they are not prone to day-to-day
changes in serum chemistry or cell counts. Therefore, DTIs may provide a more predictable
dosing regimen that allows for consistent anticoagulant effect with less bleeding compared
to UFH.
■ They have more predictable pharmacokinetics and greater reduction of thrombin
generation, as compared to UFH.
■ DTIs do not cause an immune-mediated thrombocytopenia.

Bivalirudin (Table 1)
■ It is supported by evidence derived from retrospective adult and pediatric studies.
■ It has short half-life (25 minutes) facilitating rapid titration.
■ The doses of bivalirudin need adjustment in patients with renal impairment.
■ Bivalirudin is administered as a continuous infusion with the dose ranging between 0.025
mg/kg/hr and 0.48 mg/kg/hr. It is usually titrated to target a therapeutic activated partial
thromboplastin time (APTT) range. A positive correlation was demonstrated between
bivalirudin dose and APTT.

Heparin versus Bivalirudin


Two retrospective studies compared bivalirudin to UFH and found that bivalirudin resulted in
more stable APTT measurements.
The largest study, which included both adults and children, showed better preservation
of platelet count and AT levels, less bleeding, and lower overall cost despite the higher cost of
bivalirudin.
For argatroban and lepirudin, there is not much supporting evidence. Argatroban is
contraindicated in severe liver dysfunction.5
268 Section 2  Extracorporeal Membrane Oxygenation

Table 1: Summary of supporting evidence for bivalirudin as an alternative anticoagulant.


Author Study design Result
Ranucci et al. (2011) Retrospective study ACT and APTT were more stable; PLT and
ACT 160–180 sec, APTT 50–80 sec, AT were better preserved; less bleeding;
TEG r time 12–30 min lower cost
Nagle et al. (2013) Retrospective study Positive correlation r2 = 0.267 between
dose and APTT (P = 0.044)

Pieri et al. (2013) Retrospective study APTT more stable, no difference in


bleeding, thrombosis, ECMO duration,
and mortality
(ACT: activated clotting time; APTT: activated partial thromboplastin time; AT: antithrombin; PLT: platelet)

REGIONAL ANTICOAGULATION
Regional anticoagulation for the ECMO circuit is still in the developmental stage.

Nafamostat
Nafamostat mesylate, which is a protease inhibitor of the coagulation (thrombin, Xa, and
XIIa), fibrinolytic and complement systems, has been used as a regional anticoagulant for
continuous renal replacement therapy in Japan.
Its use in ECMO has been reported in a group of 13 patients with bleeding complications
from ECMO. It was infused into the venous/drainage limb of the ECMO circuit, and
anticoagulation measured by ACT and APTT was lower in the samples taken from the patient
compared to samples taken from the circuit.6

Citrate
Citrate, long used for regional anticoagulation in continuous renal replacement therapy, is
also being evaluated for use in ECMO.7

ANTICOAGULANT-COATED CIRCUITS (TABLE 2)


Heparin-Coated Circuit
■ Many centers are using heparin-bonded or surface-treated circuits in an effort to make
their circuits more biocompatible and limit or eliminate the need for anticoagulation
during CPB and ECLS.
■ Because of a short duration of action, it not much useful for critically ill patients who
require ECLS for prolonged duration.

Nitric Oxide
■ Both prostacyclin and nitric oxide (NO), exogenously added to extracorporeal circuits
along with UFH in an effort to inhibit the interaction between platelets and extracorporeal
surfaces, have been shown to reduce platelet activation and consumption.
Chapter 31  Anticoagulation during Extracorporeal Membrane Oxygenation 269

Table 2: Summary of anticoagulation drugs.


Drug Advantages Disadvantages
Unfractionated Well known Nonlinear, variable effect
heparin Mechanism known Possible HIT induction
Easy to antagonize
(protamine)
Easy to monitor (APTT/ACT)
Low molecular weight Easy to administer Accumulation in renal
heparin Lower risk of HIT induction impairment
Can only be partially
antagonized
Not easy to monitor
(aXa levels)
Direct thrombin inhibitors Independent of AT levels No antagonist
• Bivalirudin Good dose response Ceiling effect in APTT
• Argatroban No HIT induction Could interfere with INR
Mainly renal clearance Measurement
Mainly hepatic clearance
Antiplatelet drugs Inhibit coagulation at No sufficient anticoagulation
starting point No sufficient evidence
Might reduce platelet
consumption
(ACT: activated clotting time; APTT: activated partial thromboplastin time; AT: antithrombin; HIT: heparin-
induced thrombocytopenia)

■ Nitric oxide and the creation of NO-releasing polymers have been successfully demon-
strated in a rabbit model.
■ MAHAMA/NO was the first compound to be incorporated into a polymer matrix applied to
an extracorporeal circuit that upon exposure to blood locally released NO at its surface and
without systemic heparinization.
■ The MAHAMA/NO-doped circuits showed significantly decreased platelet consumption
when compared to both the heparinized and the nonheparinized control groups.8

HEMOSTATIC ADJUNCTS
The available hemostatic agents are as follows:
■ Antifibrinolytics—tranexamic acid, aminocaproic acid, and aprotinin
■ Desmopressin
■ Recombinant factor VIIa.
In pediatric patients, tranexamic acid and aminocaproic acid have little positive evidence.
No supportive evidence has been published yet in adult ECMO population.
Desmopressin, a synthetic vasopressin analog, induces release of factor VIII and von
Willebrand factor (VWF). It reduces bleeding in adult postcardiac surgery patients who are on
aspirin. No evidence has been forthcoming for ECMO patients.
270 Section 2  Extracorporeal Membrane Oxygenation

Retrospective studies among both pediatric and adult cohorts undergoing ECMO have
demonstrated a reduction in bleeding and transfusion requirements with the use of rFVIIa.
Effective hemostasis was demonstrated in 93.3% subjects in an adult ECMO study (n = 66). The
rate of thromboembolic events was 3.3% (one case) which was not significantly different from
the control group. There was also no difference in the need for circuit change, ventilation time,
infectious complications, or survival between patients who received rFVIIa or not. However,
the use of rFVIIa is limited due to the fear that it may cause overt thrombosis in the patient or
the circuit as has been reported in small case series.9

ROLE OF BLEEDING BUNDLE


Some centers have reported success in the use of bleeding bundles involving some basic
measures as follows:
■ Ensuring correction of acidosis, hypothermia, hypocalcemia—the so-called deadly triad
■ Ensuring that platelets, coagulation factors, and fibrinogen are adequately replaced
■ Using adjuncts such as tranexamic acid, aprotinin, aminocaproic acid, and desmopressin
■ Excluding surgical bleeding prior to administration of rFVIIa.
The first dose of rFVIIa needs to be given in the presence of perfusion staff and a fully
primed backup circuit should be kept ready since the possibility of circuit thrombosis is high.

MONITORING OF ANTICOAGULATION IN EXTRACORPOREAL


MEMBRANE OXYGENATION (TABLE 3)
Routine monitoring includes:
■ ACT
■ Prothrombin time, APTT
■ Fibrinogen
■ Complete blood count.
Additional monitoring includes:
■ AT levels
■ Antifactor Xa levels
■ Thromboelastogram (TEG).
There are limitations with each test and hence, a combination of tests is required for
optimal anticoagulation management.

Activated Clotting Time


This is the preferred choice for monitoring anticoagulation in ECMO.
A minimum range of 140–220 seconds and maximum range of 170–240 seconds have been
used.

Advantages
■ Inexpensive
■ Point-of-care test, thus allowing immediate heparin titration.
Chapter 31  Anticoagulation during Extracorporeal Membrane Oxygenation 271

Table 3: Different tests to monitor anticoagulation.


Test Advantages Disadvantages
APTT Well known Interlaboratory variance
Monitoring UFH (could be excluded by
Easy to interpret using ratio)
Time consuming
ACT Bedside method Many factors influence the result
Easy to use
Immediate results
Anti-Xa assay Sensitive to UFH Time consuming
Needs calibration
Free hemoglobin and bilirubin
could be underestimated
VETs (ROTEM/TEG) Inhibit coagulation at Poor specificity and sensitivity
starting point regarding therapy adjustment
Might reduce platelet consumption
AT Gives clue about heparin resistance Heparin resistance not completely
(partial) relying on AT
Procoagulatory marker
D-dimer Prognostic value for Prognostic value for
oxygenator failure oxygenator failure
Platelet count Easy and fast No proven threshold
Platelet count does not
reflect platelet function
(ACT: activated clotting time; APTT: activated partial thromboplastin time; AT: antithrombin; ROTEM: rotational
thromboelastometry; TEG: thromboelastogram; UFH: unfractionated heparin; VETs: volume exchange
transfusions)

ACT will be inaccurate in:


■ Hemodilution
■ Hypothermia
■ Abnormalities in coagulation factors, fibrinogen, and platelets
■ Use of adjuncts such as aprotinin.
These coexisting conditions are common in ECMO patients.

Activated Partial Thromboplastin Time


■ APTT, an assessment of the intrinsic pathway.
■ This test involves the addition of platelet-poor plasma to the partial thromboplastin
reagent. The result reflects the time taken for clot formation as detected by optical or
electromechanical methods.
■ It has better correlation with heparin dose than with ACT in the neonatal, pediatric, and
adult population.
■ Target: 1.5–2.5 times (Table 1).
272 Section 2  Extracorporeal Membrane Oxygenation

Anti-Xa Assay
■ In the anti-Xa assay, known amounts of factor Xa and AT are added to the sample. Heparin
forms an inhibitory complex with AT and inactivates factor Xa.10
■ The excess amount of factor Xa remaining in the sample is inversely proportional to the
original amount of heparin.
■ Anti-Xa assay directly measures UFH activity and is considered the gold standard for
monitoring UFH in ECMO.
■ Compared with APTT, anti-Xa has a higher degree of correlation with heparin dose and
less variation.
■ Target range: 0.3–0.7 IU/mL.

Limitations
■ Accuracy of the anti-Xa assay can, however, be affected by:
– Hyperbilirubinemia
– Hemolysis
– Lipemia
■ Limited availability
■ Turnaround time of anti-Xa assays.

Evidence
■ A prospective adult ECMO study (n = 22) correlating the clinical antithrombotic effect
of ACT, APTT, and anti-Xa levels showed that every unit decrease in anti-Xa level was
associated with increased odds of developing deep vein thrombosis [OR 7.28 (95% CI:
1.61–32.94)], whereas there was no relationship with ACT and APTT.
■ A retrospective study in pediatric ECMO (n = 62) showed that patients who did not require
a circuit change had higher heparin doses and anti-Xa levels compared to patients who did
require it.
■ Each decrease of 0.01 IU/mL anti-Xa level increased the odds of requiring a circuit change
[OR 1.105 (95% CI: 1.00–1.10)].

Thromboelastogram/Thromboelastometry
■ It provides global information on the dynamics of clot development, stabilization, and
dissolution.
■ Its use is extrapolated from experience in a complex major surgery including CPB, having
shown to be associated with decreased blood product administration and mortality.
■ A prospective, observational study assessing the use of thromboelastometry (TEM) in
adult ECMO showed that reliable and timely information on hemostatic parameters could
be obtained during bleeding episodes and guide transfusion decisions.
■ A pilot study done on TEG during ECMO showed that it was associated with lower dose of
heparin compared to the standard APTT-based protocol.
■ However, there is lack of evidence supporting its routine use in ECMO with no published
threshold parameters or therapeutic goals.
Chapter 31  Anticoagulation during Extracorporeal Membrane Oxygenation 273
The order of accuracy for different monitoring tools is as follows:
Anti-Xa levels > APTT > ACT

Platelets and Fibrinogen


■ Fibrinogen levels and platelet counts also need to be monitored closely during ECMO
support.
■ Platelet counts more than 80,000 cells/mm3 and fibrinogen levels above 100 g/dL are
acceptable during ECMO support as per the current guidelines.
■ Coagulation management should be individualized based on the patients’ requirement.

D-Dimer11
■ No role of routine monitoring
■ Small studies have shown that it predicts oxygenator failure.

SUMMARY
■ During ECLS, there is continuous contact between circulating blood and foreign surface of
the extracorporeal circuit. As a result of this, the normal physiologic hemostatic balance is
shifted to a hypercoagulable state.
■ Ideally, when using antithrombotic therapy for ECLS, platelet and coagulation factor
activation should be inhibited enough to minimize clot formation in the ECLS circuit while
maintaining enough endogenous procoagulant activity.
■ Heparin is the most widely used anticoagulant.
■ But heparin has variable pharmacokinetics and chances of developing heparin resistance.
■ AT replacement is one option to counteract heparin resistance but there is no strong
supportive evidence for routine AT replacement.
■ Direct thrombin inhibitors are alternative agents, with more potency of anticoagulation
effect and more predictable pharmacokinetics.
■ Among DTIs, bivalirudin has more favorable evidence and argatroban is contraindicated
in severe liver dysfunction. Lepirudin has no supportive evidence.
■ But the major drawback of DTI is no specific pharmacological antidote.
■ Factor Xa inhibitors are under trial run.
■ Nitric oxide, prostacyclins, and NO-releasing compound-doped circuits require further
research to prove their efficacy even though they have strong physiological rationale.
■ ACT is point-of-care test and the most widely used monitoring technique; the target being
180–220 seconds. There are many confounding factors, which will influence the ACT.
■ APTT is more reliable than ACT.
■ Factor Xa levels are the most accurate parameter which will reflect the anticoagulant effect
of UFH. But availability of assay and turnaround time are the issues.
■ There are no clear-cut targets for blood product replacement. For VA ECMO, the usual
target Hb is 10 g.
■ There is no clear-cut role for antifibrinolytics in adult ECMO patients.
274 Section 2  Extracorporeal Membrane Oxygenation

■ Anticoagulant-coated circuits are evolving, but there is no major advantage as the duration
of action of UFH is short.
■ NO-releasing circuits are under development.
■ Coating the membrane surfaces with synthetic and natural polymers and endothelialization
of the membrane surfaces are two current research areas.

REFERENCES
1. Millar JE, Fanning JP, McDonald CI, et al. The inflammatory response to extracorporeal membrane
oxygenation (ECMO): a review of the pathophysiology. Crit Care. 2016;20(1):387.
2. Robinson TM, Kickler TS, Walker LK, et al. Effect of extracorporeal membrane oxygenation on
platelets in newborns. Crit Care Med. 1993;21:1029-34.
3. Extracorporeal life support organization. [online] Available from: https://www.elso.org/Registry/
SupportDocuments.aspx. [Last accessed October, 2019].
4. Bembea MM, Annich G, Rycus P, et al. Variability in anticoagulation management of patients
on extracorporeal membrane oxygenation: an international survey. Pediatr Crit Care Med.
2013;14:e77-84.
5. Pratt C, Church F. Antithrombin: structure and function. Semin Hematol.1991;28:3-9.
6. Choi JY, Kang YJ, Jang HM, et al. Nafamostat Mesilate as an Anticoagulant During Continuous
Renal Replacement Therapy in Patients With High Bleeding Risk: A Randomized Clinical Trial.
Medicine (Baltimore) 2015;94:e2392.
7. Medicine USNLo. ClinicalTrials.gov. Available online: https://www.clinicaltrials.gov/ct2/home.
8. ELSO guidelines. (2014). [online] Available from: https://www.elso.org/Resources/Guidelines.
aspx. [Last accessed October, 2019].
9. Repesse X, Au SM, Brechot N, et al. Recombinant factor VIIa for uncontrollable bleeding in patients
with extracorporeal membrane oxygenation: report on 15 cases and literature review. Crit Care.
2013;17:R55
10. Netherland Journal of Critical Care. (2017). [online] Available from: https://www.researchgate.net/
journal/1569-3511_Netherlands_Journal_of_Critical_Care. [Last accessed October, 2019].
11. Chu DC, Abu-Samra AG, Baird GL, et al. Quantitative measurement of heparin in comparison
with conventional anticoagulation monitoring and the risk of thrombotic events in adults on
extracorporeal membrane oxygenation. Intensive Care Med. 2015;41:369-70.
CHAPTER 32
Heparin and Alternatives for Anticoagulation
in Extracorporeal Membrane Oxygenation
Muralidhar Kanchi

INTRODUCTION
Among the major hemostatic goals during extracorporeal circulation, the foremost is the
inhibition of the coagulation system. Important developments have been made in producing
materials and components used in extracorporeal circulation (ECC) and the techniques
employed for extracorporeal life support (ECLS) over the past half a century. During ECC
and ECLS, there is a continuous contact of circulating blood with foreign surface of the
extracorporeal circuit. Potential bleeding and thrombotic complications occur due to lack of
ability to completely influence the interaction between blood and the biomaterials of the ECC
and ECLS. As a result of this, there is a change of the normal physiologic hemostatic balance
toward a hypercoagulable state associated with risk of bleeding and thrombosis.1

HEPARIN
Heparin is the most widely used anticoagulant for cardiopulmonary bypass (CPB) and
extracorporeal membrane oxygenation (ECMO). About 100 years ago, in 1916 to be exact, Jay
McLean, a second-year medical student, in the course of experiments to determine whether
the phospholipid component of cephalin caused clotting, discovered heparin from liver
that prolonged coagulation.2 Heparin has been used almost exclusively as the anticoagulant
for CPB for more than half a century. Heparin is a complex glycosaminoglycan that is an
inhomogeneous, rather a heterogeneous molecule; the length and side-chain composition
of carbohydrate moieties vary; the molecular weights range from 5,000 to 30,000, with most
chains between 12,000 and 19,000.3 Currently, the standard heparin is called unfractionated
heparin (UNFH). Most commercial preparations of heparin are now derived from pig intestine.
Activity of UFH is measured in units and UFH dose should not be scientifically measured in
milligrams because of the diversity of its anticoagulant activity expected from a heterogeneous
compound. The binding of UNFH to antithrombin (AT) occurs via a pentasaccharide sequence.
This sequence is present in approximately one-third of UNFH molecule. The anticoagulant
activity of heparin is exerted by its capability to enhance the effects of antithrombin III
276 Section 2  Extracorporeal Membrane Oxygenation

Flowchart 1: Actions of unfractionated heparin.

(AT III). AT III is one of the many circulating serine protein inhibitors (serpins), which counter
the effects of circulating proteases. AT III is the major inhibitor of thrombin and factors IXa
and Xa. UNFH can inhibit thrombus formation in vivo (antithrombotic activity) and prolong
in vitro clotting tests (anticoagulant activity). It also leads to clinical bleeding (antihemostatic
activity, Flowchart 1).

DOSE OF UNFRACTIONATED HEPARIN FOR EXTRACORPOREAL LIFE SUPPORT/


EXTRACORPOREAL MEMBRANE OXYGENATION
The first dose of UNFH is 50–100 units per kg body weight; this is administered as a bolus at the
time of cannulation for ECLS, and then anticoagulation is continued as a continuous infusion of
UFH during the ECLS course. The initial bolus dose of UFH may be modified based on clinical
factors such as ongoing bleeding or coagulopathy and if the patient underwent a recent surgery
under CPB and if heparin has been reversed with protamine. Activated coagulation time (ACT)
measured and when the measured ACT is 300 seconds or below, the UNFH infusion is typically
started in a dose of 7.5–20 units/kg/hr.4 This dose is adjusted at a lower dose range in adults,
and higher for pediatric and neonatal patients, unless there is excessive bleeding. UNFH may
not be started immediately in patients who are experiencing significant bleeding or who have
just had cardiac surgery. Therapeutic anticoagulation during ECLS/ECMO, classically defined
by ACT range of 180–220 seconds4 is achieved with UNFH infusion rates of 20–50 units/kg/
hr. UFH requirement may be increased by infusion of platelets, diuresis or concurrent of
renal replacement therapy. In some patients especially neonatal/pediatric, the ACT may be
fallacious leading to excessive anticoagulation and bleeding or underanticoagulation and
possible thrombosis. In such cases, the dose of infusion of UFH may be dictated by close
clinical monitoring. In some neonatal/pediatric ECLS centers, a minimum UNFH dose of
10–20 units/kg/hr and maximum UNFH dose of 40–50 units/kg/hr is being adapted as a policy,
despite the ACT value.4

THERAPEUTIC MONITORING OF UNFRACTIONATED HEPARIN


Activated Clotting Time
For over 20 years now, ACT is the most commonly used test in ECLS/ECMO to monitor UNFH
therapy in extracorporeal application to determine and titrate the dose of UNFH. The ACT is
an inclusive functional test of hemostasis and is a whole blood point-of-care test (POCT). In
this test, blood is mixed with an activator (celite, kaolin, glass beads, etc.) and the clotting time
Chapter 32  Heparin and Alternatives for Anticoagulation in Extracorporeal Membrane Oxygenation 277
is determined. ACT results may be affected by factors other than circulating UNFH, for instance,
anemia, hypofibrinogenemia, thrombocytopenia and other coagulation factor deficiencies.
The ACT is relatively inexpensive POCT that is available 24 hours in most centers. It is worth
noting that hypothermia and hemodilution can affect an ACT result.5 Additionally, different
ACT machines may give divergent results. Because of the potential shortcomings of UNFH and
the ACT when used as a stand-alone test, it may be useful to complement regular whole blood
ACT measurements with more elaborate tests of anticoagulation as discussed here.

Anti-Factor Xa Activity Levels


Unfractionated heparin is a heterogeneous molecule and its effect is varied in different
individuals. Hence, it is difficult to determine the optimal dose of UNFH to offer satisfactory,
whilst avoiding bleeding complications. Measurement of ex vivo UNFH concentrations by
protamine titration is reliable and reproducible, but this test is not readily available or easy to
automate. Many centers use anti-factor Xa activity (anti-Xa) assay as the gold standard test to
monitor and adjust the management of therapeutic UNFH and low-molecular-weight heparin
(LMWH) therapy.6 The anti-Xa assay is not a measure of UNFH concentration, but rather a
measure of UNFH effect, based on the ability of UNFH to catalyze AT’s inhibition of factor Xa.
In contrast to the ACT and activated partial thromboplastin time (aPTT), the anti-Xa assay is
specific to the anticoagulant effect of UNFH and is not influenced by coagulopathy,
thrombocytopenia or dilution. Some centers when determining the anti-Xa Assay, add
exogenous AT and this can have a profound impact on the results. However, anti-Xa assays
without exogenously added AT, are preferable since the result is dependent on the patient’s in
vivo AT activity. Most calorimetric anti-Xa assay kits are affected by conditions that can occur
in critically ill and ECLS patients. These conditions are hyperlipidemia, hyperbilirubinemia, and
high plasma free hemoglobin (hemolysis), and this results in spuriously low anti-Xa level. The
target levels of anti-Xa assay for anticoagulation in of majority of ELSO centers is 0.3–0.7 IU/mL.7

Activated Partial Thromboplastin Time


The aPTT measures the time to fibrin formation using an activator (silica and ellagic acid),
calcium, and phospholipids added to plasma, i.e. cellular components are absent. The aPTT
is a useful test for anticoagulation in ECLS when moderate doses of UNFH are used and it is
a common practice in many adult ECLS centers to prefer aPTT instead of the ACT to screen
and regulate UNFH therapy. However, aPTT is thought to be less reliable to guide heparin
therapy in infants as these subjects have prolonged aPTT values at baseline. Currently, bedside
determination of aPTT is feasible using point-of-care (POC) devices; these determinations
correlate well with anti-Xa activity assays in pediatric cardiac catheterization patients.8 The
normal value of aPTT is 30–40 seconds and during ECMO/ELSO, a value of 1.5–2.5 times
normal values will be desirable.

Thromboelastography and Rotational Thromboelastometry


The viscoelastic coagulation testing can be done using thromboelastogram (TEG®).
TEG is a comprehensive whole-blood POCT that determines the rate of clot formation and
278 Section 2  Extracorporeal Membrane Oxygenation

Box 1: Problems with heparin as an anticoagulant.


• Heterogeneity and variable potency
• AT III decrease
• Heparin resistance
• Heparin rebound
• Heparin-induced thrombocytopenia (HIT)

Flowchart 2: Coagulation and alternatives to heparin for anticoagulation.

its dissolution. It includes the part played by platelets. Information on the integrity of
coagulation cascade, platelet activity, platelet-fibrin interaction, and fibrinolysis, is obtained
in minutes. Paired TEG®/rotational thromboelastometry (ROTEM) samples with and without
the addition of heparinase (kTEG/hTEG or APTEM/HEPTEM) allow for the underlying
assessment of coagulation in the presence of UNFH. As a result, UNFH responsiveness can
be evaluated by TEG®/ROTEM by examining the difference in reaction time (R) or clotting
time (CT) between tests with and without heparinase, which may be beneficial when there is
concern for heparin resistance (ACT levels are discrepant from anti-Xa assays). Some centers
prefer replacement of AT to be based on evaluation of these parameters rather than AT activity
levels alone. Using TEG®, it is also possible to evaluate the degree of platelet inhibition using
arachidonic acid and adenosine diphosphate (Box 1).
Heparin-induced thrombocytopenia (HIT) is a potentially lethal condition that is associated
with a decrease in platelet count in excess of 30–40%. Despite this, heparin performs better than
its alternatives. However, in patients with HIT or suspected HIT, heparin is contraindicated
and we need to look for safe alternatives. The heparin substitutes currently available include
ancrod, a proteinase obtained from snake venom that destroys fibrinogen; heparin fragments,
which provide less thrombin inhibition than the parent, unfractionated molecule; direct factor
Xa inhibitors; and direct thrombin inhibitors as shown in Flowcharts 2 and 3.

ANCROD
Ancrod is obtained from snake venom; ancrod abnormally cleaves fibrinogen and destroys it.
This leads to thrombin having no substrate for it to act. Patients anticoagulated using ancrod
tend to bleed excessively and often need transfusion of cryoprecipitate and fresh frozen plasma
(FFP) more than when anticoagulated with heparin.
Chapter 32  Heparin and Alternatives for Anticoagulation in Extracorporeal Membrane Oxygenation 279
Flowchart 3: Alternatives to heparin in relation to coagulation cascade.

(LMWH: Low-molecular-weight heparin)

Ancrod is not suitable in patients on ECLS and is not commercially available in most
countries including the United States.

LOW-MOLECULAR WEIGHT HEPARIN


The length of its polysaccharide chain determines the anticoagulant activity of heparin. A
chain length longer than 18 saccharide units is required for thrombin inhibition. APTT activity
follows antifactor IIa activity more closely than it does antifactor Xa activity. Thrombin must
bind to a portion of the heparin chain for AT to inhibit it. In contrast, factor Xa inhibition by
AT does not require interaction of factor Xa with the heparin molecule. Only about 1–2% of
standard heparin consists of low-molecular-weight (molecular weight, 6,000–7,000) fragments.
LMWHs display greater antithrombotic activity and less antihemostatic activity. Unfortunately,
280 Section 2  Extracorporeal Membrane Oxygenation

coagulation tests sensitive to thrombin inhibition and insensitive to inhibition of factor Xa,
namely, the aPTT and ACT do not adequately monitor the antithrombotic effects of LMWHs.

DIRECT THROMBIN INHIBITORS


Hirudin, produced by the medicinal leech Hirudo medicinalis, is a single chain of polypeptide
that contains 65 amino acids with a molecular weight of 7,000. Hirudin binds directly to
thrombin without necessity of a cofactor or enzyme; this causes inhibition of all the proteolytic
functions of thrombin. Hirudin depends on renal excretion; renal failure prolongs its
elimination half-life of 0.6–2.0 hours. Hirudin has been used for patients with HITT, but many
of these patients have excessive hemorrhage after cardiac surgery because of the fact that the
half-life (approximately 90 minutes) is relatively long. Although there are no known direct
neutralizing agent for these drugs, administration of prothrombin complex may partially
restore coagulation by enhancing thrombin generation. Hirudin is highly antigenic and will
generate an immune response with production of immune complexes in about 40% of patients.
The incidence of anaphylaxis may be as high as 10% if it is used for a second time. Presently,
hirudin is not recommended as a primary anticoagulant for ECMO or CPB even if a patient has
HIT antibodies.
New direct thrombin inhibitors that are currently available are argatroban and bivalirudin.
Argatroban is a relatively small molecule derived from L-arginine. Argatroban acts as a
univalent direct thrombin inhibitor. It binds at the active cleavage site of thrombin and stops
thrombin’s action on serine proteases. It is completely cleared by the liver and has a half-life
of 45–55 minutes with prolongation when liver function is depressed or liver blood flow is
decreased. There is no specific reversal agent for argatroban, although factor VIIa can be given
to increase thrombin generation.

Bivalirudin
Bivalirudin is biosynthesized from hirudin and is a bivalent 20-amino acid peptide. One
active site competitively binds to the fibrinogen-binding site of thrombin; and the other end
of the molecule, the amino-terminal sequence, binds to the active serine cleavage site of
thrombin. This synthetic molecule has high affinity for thrombin and has the unique property
of binding both clot-bound and free thrombin. Bivalirudin has a short half-life; the t1/2 is
approximately 20–25 minutes in the presence of normal renal function. The most distinctive
feature of bivalirudin is that its binding to thrombin is reversible. The molecule of bivalirudin
is itself cleaved by thrombin. There is no reversal agent for bivalirudin and hence recovery of
coagulation occurs as the action as it is destroyed by thrombin (proteolytic cleavage). About
20% of the molecular activity of bivalirudin is eliminated by renal clearance.9

REFERENCES
1. Dalton HJ, Reeder R, Garcia-Filion P, et al.; Eunice Kennedy Shriver National Institute of Child
Health and Human Development Collaborative Pediatric Critical Care Research Network.
Factors associated with bleeding and thrombosis in children receiving extracorporeal membrane
oxygenation. Am J Respir Crit Care Med. 2017;196(6):762-71.
Chapter 32  Heparin and Alternatives for Anticoagulation in Extracorporeal Membrane Oxygenation 281
2. McLean J. The discovery of heparin. Circulation. 1959;19(1):75-8.
3. Casu B. Structure of heparin and heparin fragments. Ann NY Acad Sci. 1989;556:1-17.
4. Extracorporeal Life Support Organization. (2014). ELSO Anticoagulation Guideline. [online]
Available from: https://www.elso.org/portals/0/files/elsoanticoagulationguideline8-2014-table-
contents.pdf. [Last accessed October, 2019].
5. Nankervis CA, Preston TJ, Dysart KC, et al. Assessing heparin dosing in neonates on venoarterial
extracorporeal membrane oxygenation. ASAIO J. 2007;53(1):111-4.
6. Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the seventh ACCP Conference on
Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):188S-203S.
7. Bembea MM, Annich G, Rycus P, et al. Variability in anticoagulation management of patients
on extracorporeal membrane oxygenation: an international survey. Pediatr Crit Care Med.
2013;14(2):e77-84.
8. Kim GG, El Rouby S, Thompson J, et al. Monitoring unfractionated heparin in pediatric patients
with congenital heart disease having cardiac catheterization or cardiac surgery. J Thromb
Thrombolysis. 2010;29(4):429-36.
9. Cho HJ, Kim DW, Kim GS, et al. Anticoagulation therapy during extracorporeal membrane
oxygenator support in pediatric patients. Chonnam Med J. 2017;53(2):110-7.
CHAPTER 33
Monitoring during Extracorporeal
Membrane Oxygenation
Vivek Gupta, Rajeev Gupta, GS Wander

INTRODUCTION
The indication of extracorporeal membrane oxygenation (ECMO) includes various life-
threatening but reversible conditions of cardiac and/or respiratory failure. The use of ECMO
has increased significantly in the last few years with the improved outcome and lesser
complications. This is partly contributed by advancement in technology, miniaturization of
hardware, and our better understanding about this novel technology. However, this life-saving
modality is complex and the outcome depends on expertise and experience in managing
these patients on ECMO.1 An ECMO specialist must understand the physiology and have
thorough knowledge regarding hardware (circuit/oxygenator/pump head/connections, etc.)
to ensure adequate monitoring and its interpretation to make appropriate changes during
ECMO support. Continuous monitoring of both the patient and the circuit by a trained nurse
is essential. An awareness and communication of the potential issues among the team is vital
because a rapid response to critical events can prevent catastrophic consequences. A patient
supported with ECMO must be monitored continuously in an intensive care unit (ICU) setting
and include a thorough clinical examination, regular inspection of the circuit and machine,
and monitoring of hemodynamic and metabolic parameters, including but not limited to
blood gases and coagulation profile.

PHYSIOLOGY OF EXTRACORPOREAL MEMBRANE OXYGENATION


Physiology of Venovenous Extracorporeal Membrane Oxygenation
During the venovenous (VV) ECMO, blood is taken from the venous system and after the gas
exchange through the oxygenator it is returned back to the venous system of the heart (right
atrium). This blood is mixed with the native blood flow and then passes through the right
ventricle to pulmonary circulation and finally circulates throughout the body via the left side
of the heart. This is prudent to understand the mixing of two circulation with different levels of
oxygenation (ECMO and native circulation), which will determine the arterial oxygen content
in systemic circulation.2 Usually around 60% of the blood passes through the ECMO circuit
Chapter 33  Monitoring during Extracorporeal Membrane Oxygenation 283
and is sufficient to maintain oxygenation; however, if there is increase in cardiac output (CO),
the oxygen saturation will decrease. There is no direct effect of VV ECMO on cardiovascular
functions; however, indirectly it improves the hemodynamics3,4 due to reduction in ventilatory
setting, metabolic parameters and improvement in respiratory failure complicated by acute
cor pulmonale.5

Physiology of Venoarterial Extracorporeal Membrane Oxygenation


Both heart and lung are supported with venoarterial (VA) ECMO; blood is also drained through
the venous system (usually femoral vein in peripheral VA ECMO) and after gas exchange, it is
pumped back into the arterial system (usually femoral artery in peripheral VA ECMO). High
flow of VA ECMO will completely support the heart and lung in severely depressed cardiac
function. The oxygenated blood is returned through the femoral artery and reaches the aorta
in a retrograde manner and perfuses the organs. The mixing of antegrade (left ventricular
ejection) blood flow and retrograde (ECMO) blood flow usually occurs if left ventricle is still
ejecting the blood. The level of mixing will depend on the degree of cardiac dysfunction. In a
scenario, if cardiac functions are preserved even partially with impaired pulmonary function,
the coronary and cerebral vessels will be poorly oxygenated.6 This may lead to coronary and
cerebral hypoxia. In an extreme situation, there may be differential hypoxemia and upper body
cyanosis commonly called “Harlequin syndrome.”

MONITORING EXTRACORPOREAL MEMBRANE OXYGENATION SYSTEM


The monitoring of ECMO support must focus on the accuracy of ECMO setting and hardware,
efficacy of ECMO support, and ensuring safe run of ECMO. Continuous vigilance and
appropriate safety devices must be applied during ECMO support to ensure smooth function
of the circuit and machine, which is essential to achieve an adequate level of oxygen delivery
at the tissue level.7,8 The ECMO monitoring is integrated with patient monitoring to identify
any untoward event early during support. The devices which can be useful for safe ECMO run
include the following:

Blood Flow Measurement: Ultrasonic Flow Probes


Flow sensor is a crucial component of ECMO circuits which help in continuous measurement
of blood flow rate and detects the bubble. This ultrasonic flow meter is attached to the outflow
tubing to the patient. External flow probes positioned distal to all circuit shunts provide an
accurate reflection of the delivered extracorporeal pump flow.7

Extracorporeal Membrane Oxygenation Circuit Pressure Monitoring


Disposable pressure transducers may be incorporated at three locations of the ECMO circuit.
Extracorporeal Life Support Organization (ELSO) recommends pressure monitoring of the
access line (venous drainage line), preoxygenator, and postoxygenator ports of the system.7
Excessive negative pressure on the venous drainage cannula may traumatize the surrounding
tissue of the heart and vascular endothelium as well as cause an outpouring of gaseous
284 Section 2  Extracorporeal Membrane Oxygenation

emboli in venous blood from tubing cavitation. Continuous negative pressure monitoring
may be helpful in the assessment of intravascular volume status and proper venous catheter
positioning. Positive pressure monitoring helps to identify high-line resistance, so that
pump speed can be reduced to prevent circuit rupture. An elevated premembrane pressure
with normal postmembrane pressure result in elevated transmembrane pressures (or ΔP)
may signify an accumulation of fluid, thrombus, or lipids that compromise oxygenator
performance.8,9 An increase in both pre- and postmembrane pressure suggests kinking or
obstruction in the tubing or cannula after the oxygenator.

Oxygen Analyzers and Blood Gas Monitoring


Oxygen analyzers measure the fraction of oxygen delivered through the gas blender to the
membrane oxygenator noninvasively. These values should be compared with the set fraction
inspired oxygen (FiO2) settings on the blender, to identify a gas flow problem. A point-of-care
inline blood-gas monitoring system measures arterial and venous saturation to assess the
delivered oxygen content and oxygen consumption continuously.10

Temperature Monitoring
Temperature monitoring should be done continuously during ECMO support from the
patient, at the pump level, and at blood-warming device sites. Patient temperature is usually
maintained at the normal level; however, temperature management may be required in
cerebral hypoxic events to maintain mild hypothermia, rewarming in case of unintentional
cooling and shivering, and avoidance of hyperthermia from fever.6

EXTRACORPOREAL MEMBRANE OXYGENATION SYSTEM MONITORING: SAFETY,


EFFICACY, AND EFFICIENCY
The complete ECMO system from one end to the other end must be assessed at least on a
daily basis. This monitoring must look for any clots in the circuit, oxygenator, or pump head
which is suggestive of inadequate anticoagulation. The pump head must be checked for any
clicking or friction sound indicating fibrin deposition on the impeller blades. Increasing the
sweep gas flow to the maximum for a brief period (less than a second) helps in removing water
condensation from the oxygenator and helps in improving the quality of gas exchange. The
external power source must be turned off to check the battery backup on a daily basis. The
ultrasonic blood flow meter should be lubricated with gel to prevent false alarm. Emergency
equipment must be available on an ECMO cart, which includes hand crank (all staff working
in the ECMO unit must know to attach and use) and few clamps. The use of alcohol-based
solution on plastic tubing, which may lead to crack, is best avoided.
The efficacy of the ECMO system may be assessed by monitoring pressures upstream
(preoxygenator) and downstream (postoxygenator) of the oxygenator. The efficacy of the
oxygenator may be assessed by checking the pre- and postoxygenator blood gases, in case of
unexplained hypoxemia or hypercapnia. One must be vigilant for relation of the blood flow
and pump revolution/min, which is preload sensitive and afterload dependent; this will help
Chapter 33  Monitoring during Extracorporeal Membrane Oxygenation 285
to recognize any obstruction or kinking to the circuit or oxygenator.11 The cannula must be
checked for its fixation on a daily basis and after every patient movement for any displacement.
A continuous peripheral capillary oxygen saturation (SpO2) monitoring is a guide to arterial
oxygenation, especially in VA ECMO; placing the probe on the fingers of the right arm helps in
assessing the oxygenation to the brain and myocardium. During VA ECMO, frequent arterial
blood gas (ABG) analysis may be required during the nonpulsatile flow. However, during
VV ECMO once in a day ABG may be sufficient after initial stabilization. Distal perfusion
monitoring in VA ECMO is assessed by limb color and warmth compared with the other side.
However, a Doppler assessment for distal pulses should be done routinely.
The dark color urine during ECMO run should raise an alarm for hemolysis, which should
be confirmed by monitoring lactate dehydrogenase, serum bilirubin, haptoglobin, aspartate
aminotransferase, alanine aminotransferase, and plasma-free hemoglobin.
Frequent echocardiography evaluation is important to monitor right ventricular
dysfunction during VV ECMO and left ventricular distension, thrombus formation, and CO
during VA ECMO.

HEMODYNAMIC MONITORING
Patients with ECMO support require advanced hemodynamic monitoring, which not only
helps in assessing the cardiovascular functions but also assesses the effectiveness of ECMO
support as well.12 Hemodynamic monitoring helps in assessing the adequacy of organ and
tissue perfusion.13 The hemodynamic assessment is helpful at every stage of ECMO support for
appropriate decision making (Table 1).
During VA ECMO, the hemodynamic assessment should focus on a patient’s own cardiac
function using echocardiography, measuring CO, and mixed venous oxygen saturation (SvO2).
However, adequacy of tissue perfusion is guided by correction of metabolic acidosis, decreasing
lactate levels and urine output. The trend of the available hemodynamic information will
further guide the course of therapy.
Echocardiography is a quick, real-time, and noninvasive method for assessment of cardiac
function (Table 2). The CO assessment using the Swan–Ganz catheter is still considered
the gold standard of hemodynamic monitoring;14 however, other methods of monitoring
continuous CO are also available. These methods calculate CO using pulse contour analysis,
bioimpedance, bioreactance, etc. In spite of several limitations, judicious use of the pulmonary
artery catheter provides useful hemodynamic information in an ICU patient.15
Extracorporeal membrane oxygenation support should help to achieve an adequate
balance between tissue oxygen supply and demand by maintaining optimal tissue perfusion.
The SvO2, measured through the Swan-Ganz catheter, by taking an sample from the main
pulmonary artery reflects the global tissue perfusion and an SvO2 between 60% and 80% is
considered as adequate peripheral perfusion. However, this does not guarantee the adequate
regional tissue perfusion.
During VA ECMO, the oxygenated blood coming from the arterial cannula and the native
blood ejecting from the patient’s left ventricle (LV) mix with each other. This may lead to
the perfusion of less oxygenated blood in coronary arteries and cerebral arteries.16 This may
286 Section 2  Extracorporeal Membrane Oxygenation

Table 1: Checklist for hemodynamic monitoring during VA ECMO.


Parameter What to look Comment
Rhythm Ventricular fibrillation May lead to LV distension and
(absent LV ejection) thrombus formation
MAP Hypotension • VA ECMO flow not sufficient
(MAP = CO × SVR) • Low SVR
Pulsatility Lack of pulsatility on arterial waveform caused by: May result in:
• Poor myocardial function • Thrombus
• Excessive VA ECMO support • Myocardial ischemia
• Inadequate preload • Pulmonary edema
• RV failure
Flow (L/min) Low flows (assuming centrifugal pump)
• Inadequate preload
– Hypovolemia (may see hemolysis, chattering)
– Mechanical obstruction
• Excessive afterload (thrombus, kink, SVR)
• Inadequate RPM
Gas exchange Inadequate PaO2, inadequate or excessive CO2 elimination
• VA ECMO settings
– FiO2
– VA ECMO flow
– Sweep gas flow rate
• Oxygenator function
– Pre- and postmembrane pressures
– Pre- and postoxygenator gases
• Upper body hypoxemia (femoral-femoral cannulation)
Tissue oxygen Decreased SvO2 and increasing lactate suggest
delivery inadequate oxygen delivery (DO2 = CO × CaO2)
• VA ECMO flow
• Hemoglobin
• SaO2
Excessive oxygen consumption
(ER = VO2/DO2)
• Febrile
• Shivering
Distal limb • Absent pulses Dorsalis pedis and posterior
ischemia • Cyanosis and cold limb tibial artery: Not palpable
(CO: cardiac output; LV: left ventricle; MAP: mean arterial pressure; RV: right ventricle; SVR: systemic vascular
resistance; VA ECMO: venoarterial extracorporeal membrane oxygenation)

lead to myocardial ischemia and further worsening of the cardiac function. This differential
hypoxemia leading to cerebral hypoperfusion is associated with poor neurological outcome.17
A patient on VV ECMO usually has preserved cardiac function. However, there may be
preexisting right ventricular dysfunction due to chronic pulmonary hypertension or right
ventricular dysfunction may be secondary to increased pulmonary blood flow and pulmonary
vascular resistance. The VV ECMO supports the gas exchange, which should be monitored for
effectiveness of respiratory support.18
Chapter 33  Monitoring during Extracorporeal Membrane Oxygenation 287

Table 2: Echocardiographic evaluation at different stages of ECMO support.


Prior to initiation
• Cardiac function
– Decision about VA or VV ECMO
– Ruling out any contraindication such as severe aortic regurgitation or aortic dissection
After initiation
• Volume status
• Cannula position
– Access or venous cannula for inadequate drainage
– Placement of dual-lumen cannula (through the internal jugular vein) during VV ECMO
– Position of access and return cannula to prevent recirculation (VV ECMO)
During maintenance
• Daily at least once
– Cannula position
– Assessment of cardiac recovery in VA ECMO
– LV distension/LV or aortic valve thrombus during VA ECMO
– Right ventricular function, especially in VV ECMO
– Pericardial tamponade
During recovery
• Adequate LV ejection fraction
• LV outflow tract velocity-time integral >10 cm
• Thrombus
(ECMO: extracorporeal membrane oxygenation; LV: left ventricular; VA ECMO: venoarterial ECMO; VV ECMO:
venovenous ECMO)

RESPIRATORY MONITORING DURING EXTRACORPOREAL


MEMBRANE OXYGENATION
Monitoring respiratory function during VA ECMO may be challenging due to reduced blood
flow through pulmonary circulation. However, during VA ECMO, lung function may
compromise in patients having severely depressed LV function. The distension of the left
side of the heart may lead to pulmonary venous congestion and pulmonary edema. During
ECMO, it may not be clinically significant but it may lead to delayed weaning due to severe
respiratory failure.19 This may be due to a preexisting unrecognized lung injury, pulmonary
edema, or systemic inflammatory response syndrome and multiorgan dysfunction.20 A
protective lung ventilation strategy should be used to prevent ventilator-induced lung injury.
Usually, maintaining a peak inspiratory pressure less than 25 cmH2O, positive end expiratory
pressure around 10 cmH2O, and respiratory rate less than 10 per minute with an FiO2 0.3 may
be sufficient to protect the lungs.21
During VV ECMO, respiratory monitoring should focus on native lung function, adjusting
ventilation to prevent further damage, and identification of complications. Improvement of
gas exchange through the native lung is suggestive of lung recovery, which should be assessed
on a daily basis by increasing ventilator FiO2 to 1 and checking the improvement of PaO2.
Similarly, an increase in EtCO2 is considered as lung recovery.22 Monitoring the tidal volume,
plateau pressure, driving pressure, and lung compliance is important to guide the change in
the ventilatory settings and the impact of these changes on the lung function.
288 Section 2  Extracorporeal Membrane Oxygenation

METABOLIC MONITORING
Arterial blood gas monitoring for a patient on VV ECMO is similar to any other patient in ICU.
A pulse oximeter probe will help to avoid frequent ABG analysis. The arterial oxygenation is a
combination of SvO2 and intrapulmonary shunt. So, in the initial phase, the shunt fraction is
nearly 100% due to nonfunctional lungs and partial pressure of oxygen is close to SvO2.23 During
VV ECMO, oxygen saturation above 85% is acceptable as long as oxygen delivery is adequate.
Oxygen delivery (DO2) should be around three times higher than oxygen consumption (VO2)
to avoid tissue hypoxia.23,24
During peripheral VA ECMO, an arterial line should be secured on the right arm and
blood gases’ analysis should be taken from the same side. This will provide information about
oxygenation at the level of coronary, innominate, and left common carotid arteries. Oxygen
saturation monitoring should be done by placing the pulse oximeter probe on the right side
especially if arterial line placement is not possible on the right side; however, pulse oximeter
tracing may be difficult in patients with severely depressed cardiac function with nonpulsatile
ECMO flow. Venous saturation on VA ECMO is a true reflection of venous oxygen content. This
can be measured from either a central line or premembrane blood gases. This is important to
ensure that oxygen delivery is matching with oxygen consumption. A low venous saturation is
suggestive of inadequate CO and if it is associated with lactic acidosis and signs of end-organ
hypoperfusion, increasing ECMO flows may optimize oxygen delivery. However, volume status
must be optimized and transfusion may be considered, if needed.

NEUROLOGICAL MONITORING DURING EXTRACORPOREAL


MEMBRANE OXYGENATION
Neurological insult is a major contributor of morbidity and mortality during ECMO support.25
The neurological assessment includes physical assessment, laboratory, electrophysiological,
or neuroimaging. However, the clinical assessment of neurological status may be influenced
by various factors such as pre-ECMO hypotension, hypoperfusion and shock, and sedation
during ECMO. There is no guideline for the minimum neurological monitoring standard
during ECMO support. However, a high degree of suspicion and thorough evaluation will help
in identifying neurological injury early and may prevent further damage.
The pupils must be assessed several times during the day in the sedated and/or paralyzed
patient with ECMO support. The recent literature suggests that the rate of neurological
complications (stroke and bleeding) ranges from 4% to 9%.26,27
The options for imaging techniques are limited during ECMO. Transcranial Doppler
(TCD) and head ultrasound (HUS) may be useful tools for bedside imaging in a small child;
however, in adults, computed tomography (CT) is preferred and the usefulness of TCD
is restricted to monitor cerebral blood flow, identifying increase in intracranial pressure
(ICP) and microembolization.28 Magnetic resonance imaging (MRI) is not possible during
ECMO support since MRI-compatible ECMO console and consumable are not available.
CT scan had a significant impact in diagnosing, prognosticating, change in plan of care, and
decision-making for surgical intervention associated with neurological complications during
Chapter 33  Monitoring during Extracorporeal Membrane Oxygenation 289
ECMO support.29 The use of cerebral near-infrared spectroscopy (NIRS) helps in detecting
ischemic cerebral events early during ECMO support.16

SUMMARY
■ A thorough understanding of ECMO configuration and physiology is important for
cardiopulmonary monitoring during ECMO run.
■ A continuous monitoring of both patient and circuit and communication on potential
issues can prevent catastrophic consequences.
■ The ECMO system must be assessed for safety, efficacy, and efficiency.
■ A thorough assessment of patient, machine, and its integration is key to success for ECMO.

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for the American Society of Extracorporeal Technology. Report from AmSECT’s International
consortium for evidence-based perfusion: American Society of Extracorporeal Technology
Standards and Guidelines for Perfusion Practice: 2013. J Extra Corpor Technol. 2013;45(3):156-66.
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9. Maunz O, Penn S, Simon A. Emergency oxygenator change-out after massive fat embolism.
Perfusion. 2013;28(2):167-9.
10. Schreur A, Niles S, Ploessl J. Use of the CDI blood parameter monitoring system 500 for continuous
blood gas measurement during extracorporeal membrane oxygenation simulation. J Extra Corpor
Technol. 2005;37(4):377-80.
11. Park M, Mendes PV, Hirota AS, et al. Blood flow/pump rotation ratio as an artificial lung
performance monitoring tool during extracorporeal respiratory support using centrifugal pumps.
Rev Bras Ter Intensiva. 2015;27(2):178-84.
12. Guarracino F, Zangrillo A, Ruggeri L, et al. β-blockers to optimize peripheral oxygenation during
extracorporeal membrane oxygenation: a case series. J Cardiothorac Vasc Anesth. 2012;26(1):58-63.
13. Porhomayon J, El-Solh A, Papadakos P, et al. Cardiac output monitoring devices: an analytic
review. Intern Emerg Med. 2012;7(2):163-71.
14. Chatterjee K. The Swan-Ganz catheters: Past, present, and future. A viewpoint. Circulation.
2009;119(1):147-52.
290 Section 2  Extracorporeal Membrane Oxygenation

15. Barnett CF, Vaduganathan M, Lan G, et al. Critical reappraisal of pulmonary artery catheterization
and invasive hemodynamic assessment in acute heart failure. Expert Rev Cardiovasc Ther.
2013;11(4):417-24.
16. Wong JK, Smith TN, Pitcher HT, et al. Cerebral and lower limb near-infrared spectroscopy in adults
on extracorporeal membrane oxygenation. Artif Organs. 2012;36(8):659-67.
17. Slater JP, Guarino T, Stack J, et al. Cerebral oxygen desaturation predicts cognitive decline and
longer hospital stay after cardiac surgery. Ann Thorac Surg. 2009;87(1):36-44.
18. Schmidt M, Tachon G, Devilliers C, et al. Blood oxygenation and decarboxylation determinants
during venovenous ECMO for respiratory failure in adults. Intensive Care Med. 2013;39(5):838-46.
19. Aiyagari RM, Rocchini AP, Remenapp RT, et al. Decompression of the left atrium during
extracorporeal membrane oxygenation using a transseptal cannula incorporated into the circuit.
Crit Care Med. 2006;34(10):2603-6.
20. Boulate D, Luyt CE, Pozzi M, et al. Acute lung injury after mechanical circulatory support
implantation in patients on extracorporeal life support: an unrecognized problem. Eur J
Cardiothorac Surg. 2013;44(3):544-9.
21. Peek GJ, Elbourne D, Mugford M, et al. Randomised controlled trial and parallel economic
evaluation of conventional ventilatory support versus extracorporeal membrane oxygenation for
severe adult respiratory failure (CESAR). Health Technol Assess. 2010;14(35):1-46.
22. Zanella A, Mojoli F, Castagna L, et al. Respiratory monitoring of the ECMO patient. In: Sangalli F,
Patroniti N, Pesenti A (Eds). ECMO-Extracorporeal Life Support in Adults. Italia: Springer-Verlag;
2014. pp. 249-63.
23. Extracorporeal Life Support Organization (ELSO). (2013). Guidelines for adult respiratory failure
version 1.3: ELSO, Ann Arbor, MI, USA. [online] Available from: http://www.elsonet.org. [Last
accessed October, 2019].
24. Bartlett R, Zwischenberger JB. Management of blood flow and gas exchange during ECLS. In: Annich
GM, Lynch W, MacLaren G, Wilson JM, Bartlett R (Eds). ECMO-Extracorporeal Cardiopulmonary
Support in Critical Care: Extracorporeal Life Support Organization. Ann Arbor, MI: ECMO; 2012.
pp. 149-56.
25. Paden ML, Conrad SA, Rycus PT, et al.; ELSO Registry. Extracorporeal Life Support Organization
Registry Report 2012. ASAIO J. 2013;59(3):202-10.
26. Davies A, Jones D, Bailey M, et al.; Australia and New Zealand Extracorporeal Membrane
Oxygenation (ANZ ECMO) Influenza Investigators. Extracorporeal membrane oxygenation for 2009
influenza A (H1N1) acute respiratory distress syndrome. JAMA. 2009;302(17):1888-95.
27. Brogan TV, Thiagarajan RR, Rycus PT, et al. Extracorporeal membrane oxygenation in adults with
severe respiratory failure: a multi-center database. Intensive Care Med. 2009;35(12):2105-14.
28. Taylor GA, Fitz CR, Miller MK, et al. Intracranial abnormalities in infants treated with extracorporeal
membrane oxygenation: imaging with US and CT. Radiology. 1987;165(3):675-8.
29. Lidegran MK, Mosskin M, Ringertz HG, et al. Cranial CT diagnosis of intracranial complications
in adult and pediatric patients during ECMO: clinical benefits in diagnosis and treatment. Acad
Radiol. 2007;14(1):62-71.
CHAPTER 34
Mechanical Ventilation during
Extracorporeal Membrane Oxygenation
Pradip Kumar Bhattacharya, Lata Bhattacharya

INTRODUCTION
In 1972, the first successful use of extracorporeal membrane oxygenation (ECMO) was
reported in a patient with posttraumatic acute respiratory distress syndrome (ARDS).1 The
first prospective randomized controlled trial on ECMO funded by National Institutes of Health
(NIH) in 1974 compared venoarterial ECMO with conventional mechanical ventilation (MV) in
patients with severe ARDS. It was published in JAMA, 1979. The outcome of the study showed a
very high mortality in both the arms which was beyond 90%.
Ted Kolobow created a model in his research facility at the NIH that turned into the
primary commercially available membrane lung, and he was one of the most experienced
researchers in this field.2 Dreyfuss D indicated out that the methodology ventilation ought
to be reexamined to consider that gas trade through the native lung was never again
fundamental. High airway pressure and high tidal volume (VT), an absolute necessity to
“upgrade” gas trade through the native lung, were proposed to cause what later ended
up being known as ventilator-induced lung injury (VILI).3 The objective of ECMO was
reimagined from “purchasing time for the lung to recuperate”4 to “rest the lung”.5 Around the
same time, Gattinoni and associates presented a novel extracorporeal life support (ECLS)
method called low-frequency positive-pressure ventilation with extracorporeal carbon
dioxide evacuation (LFPPV ECCO 2 R).6 MV and the ventilator management of the native
lung assume a focal job during ECMO. By and by, shockingly, this perspective has started
getting less consideration.7-13 Most investigations report just ventilator setting and respiratory
mechanics information before ECMO; few examinations report likewise information with
respect to the first day of ECMO; and not many investigations broaden the depiction of
ventilator parameters past the first day.
There are no clinical proof-based rules prescribing a solid type of ventilation in patients
exposed to VV ECMO, however, 77% of the centers with experience apply the “lung rest”
idea, with low VT, low respiratory recurrence (RF), and high positive end-expiratory pressure
(PEEP).9
292 Section 2  Extracorporeal Membrane Oxygenation

PATHOPHYSIOLOGY OF GAS EXCHANGE DURING


EXTRACORPOREAL LIFE SUPPORT
During venovenous extracorporeal membrane oxygenation (VV ECMO) the artificial
oxygenator and the native lung are in series arrangement. Venous blood is occupied from the
venous compartment toward the counterfeit oxygenator, which gives oxygenation of blood
and CO2 expulsion. The blood then comes back to the right atrium of the patient.14
Gas exchange through the oxygenator membrane depends on different factors—oxygen
and carbon dioxide pressure gradient between the flow and the blood, membrane surface area
and the intrinsic performance, and characteristics of the membrane.
If the CO2 content of blood is high, e.g. 500 mL of venous blood contains around 250 mL/
min, it will permit smooth CO2 evacuation even at low blood flow (BF).
The sweep gas flow lessens the partial pressure of CO2 inside the empty fibers and in this
manner, expands the slope pressure among gas and blood. The sweep gas flow ventilating the
artificial lung is then the primary determinant of the measure of CO2 evacuated. Expulsion
of CO2 through the film lung empowers to decrease the respiratory moment volume thus
reducing the VT/plateau pressure (Pplat) and/or respiratory rate (RR), thus maximizing the
possibility of protective ventilation.
Then again, oxygen dissolvability in plasma is negligible (0.003 mL/mm Hg per 100 mL of
blood) and the oxygen content in the blood is constrained by hemoglobin concentration and
saturation. Blood leaves the peripheral tissues with a low substance of oxygen.
The ECMO circuit pulls back piece of the venous blood toward the membrane lung, and
the blood coming back to the right heart is the consequence of both oxygenated extracorporeal
blood and deoxygenated venous return. The immediate impact of VV ECMO on oxygenation is
increase of the mixed venous saturation of the blood coming back to the patient lung.
The measure of delivered oxygen is legitimately identified with the measure of BF in the
ECMO in respect to add up to patient cardiac output, and conversely identified with the oxygen
saturation of BF drained. Subsequently, for the ventilator setting, oxygenation backing given
by ECMO may permit decrease of ventilator FiO2 and PEEP (Flowchart 1).
Over the last decade, literature has widely focused on the indications, timing, complications,
and the effects on outcome. MV and the ventilator management of the native lung play a
central role during ECMO. Nevertheless, surprisingly, this aspect has received little attention.
Most studies report only ventilator setting and respiratory mechanics data before ECMO;
few studies report also data regarding the first day of ECMO (Table 1); and very few studies
extend the description of ventilator parameters beyond the first day. For these reasons, it is
very difficult to recognize and reproduce specific ventilator approaches; there are not enough
data to compare different studies and to support a specific ventilatory approach. Even less
information is available on how respiratory monitoring is accomplished.7,8,10,12,15-23
Artificial lung and native lung both participate in gas exchange. The amount of ECMO
blood flow (ECMO BF), and then choice of ECMO equipment and cannula size, depends on the
residual gas exchange function of the native lung, which ultimately depend on the ventilator
settings we choose (Flowchart 1). Conversely, the degree of native lung rest we may achieve
in terms of minute ventilation and airway pressure will depend on the efficiency of ECMO in
delivering oxygen and removing CO2 (Table 1).
Flowchart 1: An algorithmic approach of ventilator settings during ECMO.

Tidal volume (VT) is decreased, targeting a safe plateau airway pressure or targeting a predefined VT value (ultra-lung protective ventilation). After
adjusting VT, respiratory rate (RR) may be changed according to PaCO2/pH or target to a fixed low level (5–10 bpm). Decrease of VT and RR are allowed by
CO2 removal mainly modulated by acting on sweep gas flow (GF). This is feasible both with ECMO or ECCO2R.
When high ECMO blood flows (BF) are used, oxygenation is supported, and FiO2 may be decreased. PEEP may either be decreased if a total lung rest
strategy is used, or may be set to avoid de-recruitment associated to low VT ventilation.
Chapter 34  Mechanical Ventilation during Extracorporeal Membrane Oxygenation
293
294 Section 2  Extracorporeal Membrane Oxygenation

Table 1: Setting of PEEP, VT, respiratory rate, and FiO2 before and 24 hours after VV ECMO under various trials.
TV/PBW (mL/kg) or
PEEP (cm H2O) TV (mL) RR (bpm) FiO2
Pre During Pre During Pre During Pre During
Study Type of study N EMO ECMO ECMO ECMO ECMO ECMO ECMO ECMO
Frenckner Single center 38 13 NR 610 NR NR 10 >0.9 0.4
B8 observational (0–20) (280–
study 950)
CESAR Multicenter 68 13.7 10–15 NR NR NR 10 NR 0.3
trial.15 randomized (9.6)
trial
Brogan ELSO Registry 600 12 10 NR NR 20 10 NR 0.5
et al.16 report (10–17) (8–14) (15.25) (0.4—
0.51)
Holzgraefe Single center 13 17 <5 545 <200 NR NR 1 0.6
et al.17 observational (15–20) (408– (0.46–
study 617) 0.63)
Patroniti Retrospective 60 16 16 6.2 4.6 25 10 1 (1–1) 0.6
et al.18 multicenter (14–19) (14–19) (4.7–7.7) (3–6.3) (22–28) (8–12) (0.4–
cohort analysis 0.8)
Bonacchi Randomized 30 13.2 10–15 NR NR NR 4–10 0.99 <0.5
et al.19 single center (3.5) (0.07)
analysis
Bein Multicenter 40 16.1 (3) NR 5.9 (1.2) 3 22.4 (3) 10–25 0.62 NR
et al.20 randomized (0.2)
trial (AV
ECCO2R)
Pham Retrospective 123 13 (4) 13 (4) 6.7 (1.6) 3.9 (1.4) 27 (6) 19 (8) NR NR
et al.21 multicenter
cohort analysis
Kipping Retrospective 18 18 18 5.4 3.2 NR NR NR NR
et al.22 single center (14.5– (16.0– (3.2–7.0) (2.4–4.7)
analysis 24.5) 24.5)
Schmidt Retrospective 168 13.6 12.7 6.3 (1.5) 3.9 (1.5) 22 15 NR NR
et al.12 analysis of (4.0) (2.9) (18–30) (10–25)
multicentric
registry
Marhong Systematic 2.0 14 12 6.1 3.9 (3–5) NR NR 0.99 0.4
et al.10 review (42) (12.3– (9.2– (5.9–6.6) (0.89– (0.3–
16.1) 14) 1) 0.5)
Serpa Neto Individual 545 13.7 (4) 12.9 6.0 (1.9) 4.0 (1.7) 21.9 17.8 (8) 0.90 0.69
et al.7 patient (3.4) (7.9) (0.17) (0.24)
data meta-
analysis of
observational
studies
Combes Multicenter 124 11.7 11.2 6.0 (1.3) 3.4 30.7 23 NR NR
et al.23 randomized (3.9) (3.9) (3.4)
trial
(ECMO: extracorporeal membrane oxygenation; ELSO: extracorporeal life support organization; PBW: predicted
body weight; PEEP: positive end-expiratory pressure; V T: tidal volume; VV ECMO: venovenous extracorporeal
membrane oxygenation)
Chapter 34  Mechanical Ventilation during Extracorporeal Membrane Oxygenation 295
Some of the terminologies, which are used by various authors with respect to ventilatory
strategies during ECLS, are “lung rest” or “ultraprotective ventilation”. These are variably
and sometimes interchangeably used when referring to protective ventilatory strategies.
“Ultraprotective ventilation” has been more often utilized when referring to strategies mainly
characterized by decrease of VT, accompanied or not accompanied by a decrease in RR. “Lung
rest” is more indefinite, and even more imprecise, as it is utilized indifferently to describe a low
VT ventilation with or without a decrease in PEEP and mean airway pressure. “Total lung rest”
is a strategy combining ultraprotective ventilation with low level of PEEP.11-14,24-26

EXTRACORPOREAL LIFE SUPPORT ORGANIZATION GUIDELINES27


For the initial 24 hours, moderate-to-substantial sedation and pressure-controlled ventilation
with PEEP 15 and peak airway pressure of 25 cm H2O is proposed alongside an RR of 5 bpm. Be
that as it may, there are no particular points of confinement to the degree of PEEP given that
negative hemodynamics impacts are evaded. Following 24–48 hours, lower levels of pressure
(PEEP 10 and peak airway pressure of 20 cm H2O) are prescribed, and utilization of light
sedation in unconstrained breathing is proposed.
There is no particular proposal about VT setting, and Pplat and RR are the main prescribed
ventilator targets. Second, the progressive decline in PEEP down to 10 cm H2O perceives the
risk of too quick lessening in PEEP after ECMO beginning.

RANDOMIZED CONTROLLED TRIAL


In the CESAR (Conventional ventilatory support vs Extracorporeal membrane oxygenation
for Severe Adult Respiratory failure) trial, ECMO framework was intended to give high BFs
capacities (>5 L/min) and full substitution of respiratory gas exchange. Ventilator setting was
focused to top inspiratory pressure of 20 cm H2O, utilizing PEEP of 10 cm H2O, RR of 10 bpm,
and FiO2 of 30%.15
In the EOLIA (ECMO to Rescue Lung Injury in Severe ARDS) trial preliminary VT was
focused to restrict Pplat beneath 24 cm H2O along with a PEEP of minimum 10 cm H2O and FiO2
of 0.3–0.5.23 The distributed examination and the accessible information supplement give a
full report of ventilator parameters, including significant respiratory mechanics factors, e.g.
respiratory compliance (Crs), previously and during ECMO.

OBSERVATIONAL STUDIES
Pressure controlled is the favored method of ventilation. A typical pattern in the wake of
beginning ECMO for recalcitrant hypoxia is the diminishing of VT and FiO2 with or without
decline in RR. If there is an indication of extracorporeal CO2 removal (ECCO2R), FiO2 is left
unaltered. Setting of PEEP relies upon the ventilatory system (complete lung rest versus
anticipation of alveolar de-recruitment).7,8,10,12,16,18-22,25,28

SETTING OF TIDAL VOLUME


The abatement in VT brings about reduction in both Pplat and driving weight. Hypothetically, a
full high stream ECMO may give enough CO2 expulsion to for all intents and purposes dispense
296 Section 2  Extracorporeal Membrane Oxygenation

with the requirement for any ventilation and adventure an absolute rest lung procedure. In any
case, no examination has investigated this probability.
Serpa Neto et al.7 gathered individual information of 545 patients from nine examinations.
VT was diminished in the initial 24 hours after ECMO from 6 mL/kg to 4 mL/kg. This led to a
decline in Pplat and driving pressure of around 5 cm H2O.
Schmidt et al. gathered information, reflectively, from three master focuses (two Australians
and one French).12 VT was diminished from 6.3 ± 1.5 to 3.9 ± 1.6. Pplat and driving weight
declined by around 5 cm H2O in normal.
Pham et al.21 demonstrated that a high Pplat on the primary day of VV ECMO for intense
respiratory failure was fundamentally connected with mortality.
Bein et al.20 first investigated the feasibility of ventilating with 3 mL/kg.
Fanelli V et al.25 investigated the likelihood of bringing VT down to 4 mL/kg utilizing ECMO
frameworks ready to keep running at BFs as low as 300–400 mL/min in patients in whom
oxygenation is not seriously impeded.

RESPIRATORY RATE
Distributed information demonstrates a normal or moderate decrease in RR. Two unique
patterns were watched—some within objective of low RR (5–10 bpm) and others lessening
RR modestly. This is most likely to dodge hypocapnia that may result from the CO2 expulsion
effectiveness of ECMO.

FiO2
For high BF ECMO, it gives adequate oxygenation support; thus FiO2 and PEEP can be
diminished. Like RR, decrease of FiO2 additionally demonstrates a scope for focus fluctuation.
In case of “complete lung rest” technique there is no helpfulness of regulating FiO2.

POSITIVE END-EXPIRATORY PRESSURE


Marhong JD et al. in his survey reported that 47% of centers aimed at reducing PEEP to lower
than 10 cm H2O.10
Increment of PEEP is related with a decline in driving and Pplat and dynamic strain. PEEP
balances out the alveoli and shields them from atelectrauma. These contemplations are
significant during VV ECMO, where the utilization of extremely low VT and RR causes alveolar
flimsiness and lung breakdown.
Protti et al.29 in their animal study demonstrated that at equivalent degree of harmful total
strain, blend of high static and low dynamic strain (i.e. high PEEP and low VT) was related with
less VILI contrasted with use of low static and high dynamic strain. They inferred that VILI was
predominantly connected with dynamic strain, and that static strain may likewise assume a
defensive job.
Schmidt et al.12 showed a higher PEEP level in the first 24 hours after ECMO were associated
with better survival.
While selecting PEEP following points need attention to avoid overinterpretation:
■ Published data show a very moderate decrease in the average PEEP (around 1–2 cm H2O)
in the first 24 hours of ECMO.
Chapter 34  Mechanical Ventilation during Extracorporeal Membrane Oxygenation 297
■ There is a wide range variability in the average PEEP even before ECMO (from 12 cm H2O
to 18 cm H2O), reflecting the center-by-center differences in PEEP criteria before ECMO.
Theoretically, larger alveolar collapse and more detrimental effects on the lungs are
expected after bigger and faster reduction in PEEP.
■ Independently from any other ventilator parameter PEEP level is the main determinant of
residual lung function. At low PEEP level, native lung contribution may become minimal
and patient oxygenation totally dependent on ECMO.
■ Extensive lung collapse may lead with time to extreme pulmonary vasoconstriction,
refractory pulmonary hypertension, and right heart failure that may require conversion
from VV to VA ECMO.

PRONE POSITIONING OF PATIENTS DURING ECMO


There is proof that prone positioning during ECMO is protected whenever performed
appropriately.30,31 Prone positioning can be effectively performed during ECMO, and it is
related with improved respiratory parameters. In 17 subjects experiencing VV ECMO who
likewise flopped in any event one weaning endeavor, prolonged prone positioning (24
hours) was performed.32 Compliance increased from 18 (12–36) mL/cm H2O to 32 (15–36)
mL/cm H2O (P < 0.0001), and the PaO2/FiO2 ratio increased from 111 (84–128) mm Hg to 173
(120–203) mm Hg (P < 0.0001). Comparative studies were accounted for in a few case reports
and observational studies.33–36 Signs of prone positioning during ECMO incorporate hard-
to-wean, serious hypoxia (PaO2/FiO2 < 70) and harmful ventilator setting with level weight
surpassing 32 cm H2O.

BLOOD GAS MONITORING


Contribution of native and membrane lung determines both PaO2 and PaCO2 and it may not be
used to assess the lung function. Hence, traditional records of oxygenation, for example, PaO2/
FiO2, have little benefit during VV ECMO.
Given the generally low VT, moment ventilation capnography may likewise be of restricted
utility. Still some significant data might be inferred if day-by-day changes are carefully
screened.37
On the oxygenation side, an intriguing methodology is to screen on everyday schedule the
impact of managing FiO2 of 100% on the ventilator side. At the point when the lung capacity is
hindered and the commitment of local lung is low, setting FiO2 to 100% will have negligible or
no consequences for PaO2. Be that as it may, as the lung capacity improves the organization of
a high FiO2 will bring about increment in PaO2. On comparative way, end tidal-CO2 (ETCO2)
might be exceptionally low during VV ECMO. Be that as it may, as the lung capacity improves
ETCO2 will increase.

NEW MONITORING SYSTEMS


Franchineau et al. have evaluated the likelihood of titrating PEEP level during ECMO by
electrical impedance tomography (EIT).38 Fifteen patients experienced a decremental PEEP
298 Section 2  Extracorporeal Membrane Oxygenation

preliminary from 20 cm H2O to 0 cm H2O. EIT inferred parameters were utilized to measure at
each PEEP level the level of breakdown and overdistension. They found a wide changeability
in the ideal PEEP level and finished up on the need of individualization of ventilator setting
during ECMO.
Grasso et al. evaluated the likelihood of distinguishing patients requiring ECMO by
estimating transpulmonary weight in 14 patients with serious ARDS alluded for ECMO.39
In seven cases, the transpulmonary pressure was lower than 25 cm H2O (thought about a
protected level). In these patients, PEEP was raised from 17.9 ± 1.2 cm H2O to 22.3 ± 1.4 cm H2O
to get an objective transpulmonary pressure of 25 cm H2O. As the oxygenation improved, these
patients were effectively overseen without ECMO. On other seven patients, transpulmonary
pressure was higher than 25 cm H2O and all patients got ECMO.

SUMMARY
The optimal ventilator strategy during ECMO continued to be debated. The idea of VILI
and the requirement for defensive ventilation has picked up notoriety following the early
exploratory work of Kolobow and Dreyfuss. In light of accessible information, the most sensible
methodology is decrease of VT to safe degree of Pplat, decrease of RR to direct levels (10–15 bpm),
and keep up moderate degrees of PEEP focused in counteracting alveolar de-recruitment and
maintaining a strategic distance from overdistension. The pragmatic use of these ideas in the
patient experiencing ECLS, however dependent on strong pathophysiological grounds, needs
anyway enough logical proof to permit the illustration of rules or proposals.

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difference between statics and dynamics? Crit Care Med. 2013;41(4):1046-55.
300 Section 2  Extracorporeal Membrane Oxygenation

30. Voelker MT, Jahn N, Bercker S, et al. Prone positioning of patients during venovenous extracorporeal
membrane oxygenation is safe and feasible. Anaesthesist. 2016;65(4):250-7.
31. Goettler CE, Pryor JP, Hoey BA, et al. Prone positioning does not affect cannula function during
extracorporeal membrane oxygenation or continuous renal replacement therapy. Crit Care.
2002;6(5):452-5.
32. Kimmoun A, Roche S, Bridey C, et al. Prolonged prone positioning under VV-ECMO is safe and
improves oxygenation and respiratory compliance. Ann Intensive Care. 2015;5(1):35.
33. Litmathe J, Sucker C, Easo J, et al. Prone and ECMO -a contradiction per se? Perfusion.
2012;27(1):78-82.
34. Masuda Y, Tatsumi H, Imaizumi H, et al. Effect of prone positioning on cannula function and
impaired oxygenation during extracorporeal circulation. J Artif Organs. 2014;17(1):106-9.
35. Kredel M, Bischof L, Wurmb TE, et al. Combination of positioning therapy and venovenous
extracorporeal membrane oxygenation in ARDS patients. Perfusion. 2014;29(2):171-7.
36. Guervilly C, Hraiech S, Gariboldi V, et al. Prone positioning during veno-venous extracorporeal
membrane oxygenation for severe acute respiratory distress syndrome in adults. Minerva
Anestesiol. 2014;80(3):307-13.
37. Zanella A, Mojoli F, Castagna L, et al. Respiratory monitoring of the ECMO patient. In: Sangalli F,
Patroniti N, Pesenti A (Eds). ECMO-Extracorporeal Life Support in Adults. Italy: Springer-Verlag;
2014.
38. Franchineau G, Bréchot N, Lebreton G, et al. Bedside contribution of electrical impedance
tomography to setting positive end-expiratory pressure for extracorporeal membrane oxygenation-
treated patients with severe acute respiratory distress syndrome. Am J Respir Crit Care Med.
2017;196(4):447-57.
39. Grasso S, Terragni P, Birocco A, et al. ECMO criteria for influenza A (H1N1)-associated ARDS: role
of transpulmonary pressure. Intensive Care Med. 2012;38(3):395-403.
CHAPTER 35
Sedation and Pain Management on
Extracorporeal Membrane Oxygenation
Babu Abraham, Ajay Padmanaban

INTRODUCTION
Sedation and pain management are important considerations in patients receiving
extracorporeal membrane oxygenation (ECMO), and no evidence-based guidelines for their
use exist at this point of time. The principles of use of sedation are similar for both critically
ill patients and those on ECMO. Reducing the dose of sedation by use of protocols that
incorporate daily interruption have shown to improve outcomes.1 In addition to minimizing
oxygen consumption and improving patient–ventilator synchrony, sedation has been shown
to diminish pain, stress, and discomfort in patients on ECMO. This also helps in preventing
device dislodgement.2 Extracorporeal circulation has an effect on drug pharmacokinetics,
which influences the way sedatives and analgesics act in a patient on ECMO. This chapter will
discuss these differences and touch upon newer approaches to managing an awake patient on
ECMO, which facilitates mobilization.

PHARMACOLOGICAL CHALLENGES
Drug therapy in ECMO patients is complicated by the dual effect of critical illness and the
unique interaction that the drugs have with the ECMO (Flowchart 1).
Extracorporeal membrane oxygenation therapy affects drugs by raising the volume of
distribution (Vd) by causing hemodilution in its circuit and by sequestration of the drugs in
the components of the ECMO circuit.

Hemodilution
Priming of ECMO circuit with plasma, saline, or albumin causes hemodilution affecting the
Vd of hydrophilic drugs, which decreases their plasma concentrations.3 Hemodilution also
dilutes plasma proteins affecting the Vd of lipophilic drugs by increasing their free fraction and
thereby risk of toxicity.
302 Section 2  Extracorporeal Membrane Oxygenation

Flowchart 1: ECMO in critical illness.

(ECMO: extracorporeal membrane oxygenation)

Sequestration of Drugs
Drugs, which are lipophilic in nature and extensively protein bound, are most affected because
of sequestration in the ECMO circuit. The extensive surface areas of the ECMO circuit and
membrane oxygenator are ideal sites for sequestration of most lipophilic drugs.4 In addition,
drugs such as propofol that have high octanol/water partition coefficient (logP) are soluble in
organic material like polyvinyl chloride. For drugs that are equally lipophilic, their respective
protein binding capacity determines how much of the drug can be recovered. The priming
fluids contain proteins and blood also has plasma proteins, both attach themselves to the
circuit. Highly protein-bound drugs will then bind to the attached proteins in the circuit leading
to sequestration.5 So drugs that are both highly lipophilic and protein bound, like fentanyl, are
extensively sequestered in the circuit leading to reduced drug concentrations (Flowchart 1).

SEDATION AND ANALGESIA IN EXTRACORPOREAL MEMBRANE OXYGENATION


The 2013 guidelines for the management of pain, agitation, and delirium in the critically ill
patient have emphasized on an “analgesia first” approach to sedation.1 Pain in critically
ill patients leads to increase in the levels of pro-inflammatory cytokines causing arteriolar
vasoconstriction and tissue hypoperfusion. Opioids, in turn, reduce tissue oxygen consumption
by ameliorating this response. Management of acute pain is also important to prevent chronic
pain and post-traumatic stress disorder.
Chapter 35  Sedation and Pain Management on Extracorporeal Membrane Oxygenation 303

Opioids
Intravenous opioids have been the linchpin of analgesia in the intensive care unit (ICU). With a
rapid onset of action and short half-life, fentanyl is one of the most preferred opioids in the ICU.
However, fentanyl is extensively sequestered to the ECMO circuit as it is very lipophilic. This
is also observed with its derivatives such as sufentanil, remifentanil, and alfentanil. A study
measuring the 24-hour concentrations of fentanyl in ECMO reported that only 3% of fentanyl
was detectable at 24 hours and in the first hour up to 70% of fentanyl was lost in the circuit.5
This high level of sequestration of fentanyl can lead to high dose of the drug being needed to
achieve desired levels of analgesia. This can clinically lead to treatment failure and even opioid
withdrawal in patients who were already on high dose of the drug prior to initiating ECMO.
Morphine, being hydrophilic theoretically, should have less sequestration and better
bioavailability.5 However, some of its attributes such as histamine release, longer half-life,
and accumulation of active metabolite (morphine-6-glucuronide) in renal failure make it less
preferable as an analgesic in critical care. Opioids with agonist-antagonist qualities have poor
analgesic efficacy. They can also trigger opioid withdrawal in opioid-dependent patients.

Analgesia and Sedative Adjuncts


Ketamine and dexmedetomidine are drugs that have both analgesic and sedative effects and offer
an option to decrease both the dependence on opioids and reduce the side effects of opioids.
Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, which can augment
opioid analgesia without decreasing sympathetic tone. An infusion of ketamine can be used to
optimize patient comfort without compromising on hemodynamics and even help decrease
the dose of opioid. A single center retrospective review of ketamine used for sedation in ECMO
patients revealed a decreased requirement for vasopressors. Also, the sedation goals were met
with a cumulative lower sedation requirement. The dose of ketamine used was much higher
(50–150 mg/hr) than described in other studies of non-ECMO patients. However, there is
very limited data for use of ketamine for prolonged sedation in ICU patients. Ketamine is also
lipophilic and would be sequestered in the ECMO circuit.6
Dexmedetomidine is a selective alpha-2 receptor agonist. It has sedative and analgesic
property. Patients sedated with dexmedetomidine have reduced delirium, are calm, and have
less respiratory depression and reduced sympathetic tone.7 Dexmedetomidine also has a
tendency to be sequestered to the ECMO tubing. One study observed as much as 93% loss of
the drug at 24 hours.8
Another selective alpha-2 agonist with sedative properties similar to dexmedetomidine
is clonidine. It is less commonly used because of better hemodynamic stability offered by
dexmedetomidine. Clonidine has not been extensively studied in ECMO patients except for
one study evaluating clonidine in pediatric patients on veno-venous ECMO, which noted
increased clearance of the drug.9

Benzodiazepines
Benzodiazepines should be considered when a sedation regimen based on analgesia alone
becomes inadequate to provide patient comfort or if the clinical situation needs a greater
304 Section 2  Extracorporeal Membrane Oxygenation

depth of sedation. Benzodiazepines cause anxiolysis, amnesia, and sedation by activation of


gamma-aminobutyric acid (GABA) receptors. However, they have been implicated as a cause
of delirium and hence prolonging hospital stays.10
Midazolam is the most frequently used benzodiazepine in the ICU. It has a fast onset of
sedation and comparatively short half-life. However, it is highly lipophilic too and is sequestered
in the ECMO circuit. Studies have shown that 11–13% of midazolam was detected after 24
hours in ECMO circulation, of which 50% was lost in the first hour.5,11 Other in vitro studies
observed up to 68% loss of midazolam within 40–120 minutes of circulation.12 Midazolam and
its metabolites, which are also active, have been seen to accumulate in patients with renal and
hepatic dysfunction leading to prolonged sedation and respiratory depression.
Lorazepam is less lipophilic but has a longer half-life. In vitro studies have observed up to
30% loss of lorazepam within 40–120 minutes of circulation.12

Propofol
Propofol is an anesthetic agent that acts by potentiating GABA-A receptor activity. It is used for
ICU sedation under very close monitoring. It is highly lipophilic and is extensively sequestered
in the circuit, with only 30% of the drug remaining at 30 minutes and concentrations at 24
hours being negligible and limiting drug efficacy.11 This along with its propensity to cause
hypotension makes it an inferior option for sedation in ECMO patients. Other concerns such
as hypertriglyceridemia, propofol infusion syndrome, and hemolysis also exist. Propofol has
also been previously suspected to cause occlusion of the membrane oxygenator resulting in
oxygenator failure while being used in cardiopulmonary bypass, though this has never been
observed during ECMO use.13

TITRATION OF SEDATION IN EXTRACORPOREAL MEMBRANE OXYGENATION


The principles of sedation and analgesia use in ECMO therapy remain the same as those for
a critically ill ICU patient. The protocols used for assessment of pain and agitation and their
management in critically ill patients have clearly shown to reduce the length of mechanical
ventilation, decreasing pain and agitation and decreasing the incidence of nosocomial
infections.14 In ECMO patients, behavioral scales like the behavioral pain scale and the critical
care pain observation tool have been validated.15 The Richmond Agitation–Sedation Scale
(RASS) and the sedation-agitation scale (SAS) are dependable for titrating sedation in ECMO
patients too. In patients who are sedated and paralyzed chemically, monitoring systems such
as bispectral index (BIS) or state entropy could be considered (Flowchart 2).
Clinically, a trend has been noted toward increased requirements of sedation and
analgesia over time in ECMO patients. Multiple small studies have noticed this association
irrespective of the drug used.16,17 The reason for this increasing requirement of sedative doses
is still under evaluation and various causes such as material of circuit, tolerance, age, and
pharmacogenomics have been postulated. However, a recent prospective cohort study that
used protocolized analgosedation approach, which used nonbenzodiazepine-based sedation
regimens and lessened sedation goals, showed overall reduction in sedation/analgesia dose
requirements with no increase in its requirement through the duration of the ECMO.18 The
Extracorporeal Life Support Organization (ELSO) has made certain recommendations for
Chapter 35  Sedation and Pain Management on Extracorporeal Membrane Oxygenation 305
Flowchart 2: ECMO sedation algorithm.

(CAM: confusion assessment method; ECMO: extracorporeal membrane oxygenation; ICU: intensive care unit;
RASS: richmond agitation–sedation scale; SAT: spontaneous awakening trials; SBT: spontaneous breathing trials)

sedation use.19 They recommend that the patient be deeply sedated during cannulation to the
extent of light anesthesia and this is to prevent complications such as air embolism during
cannulation due to spontaneous breathing, to avoid technical difficulty with cannulation due
to patient movement, to decrease oxygen consumption, and to ensure patient comfort.
306 Section 2  Extracorporeal Membrane Oxygenation

Once the cannulation has been done and the patient is on the ECMO, it is prudent to stop
all sedation and narcotics to assess the neurological status. Once assessment is complete,
sedation can be resumed and titrated to the patient’s pain, anxiety, and discomfort.
Like in all critically ill protocolized sedation with daily interruptions, clear goals, and
targets, down-titrations help minimize the deleterious effects of sedation.20 After 48 hours of
ECMO, once the patient’s condition is stable, minimal to no sedation is encouraged. At the time
of ECMO discontinuation, it is important to reduce the dose of sedation as there will be a rapid
decrease in the volume of distribution, which can result in overdosage of the medications.

AGITATION AND DELIRIUM IN EXTRACORPOREAL MEMBRANE


OXYGENATION PATIENTS
Delirium is very common in ECMO patients and the incidence has been reported to be as high
as 58%.21 It is an independent predictor of inferior short- and long-term ICU outcomes and
specifically in patients on ECMO, delirium-related device dislodgement can be catastrophic.
Care should focus on monitoring, prevention, and management of delirium. The confusion
assessment method for the intensive care unit (CAM-ICU) and the intensive care delirium
screening checklist (ICDSC) are the most commonly used monitoring scales. Preventive
measures should target iatrogenic causes of delirium and minimize risk factors. Daily
assessment of sedation requirements and choosing sedatives appropriately are important for
prevention. Early mobilization along with the strategy to weaning from ECMO and liberation
from mechanical ventilation are also important in the prevention and treatment of delirium.
Factors such as deep sedation, lack of mobilization and physical therapy protocols, and
femoral cannulation delay early mobilization.21 There is emerging evidence, especially in
patients awaiting lung transplantation, that active physical therapy, including ambulation, can
be managed safely and reliably in ECMO patients.22

SUMMARY
Extracorporeal membrane oxygenation therapy causes shifts in the volume of distribution, due
to hemodilution and sequestration in the circuits leading to changes in the pharmacokinetics
of hydrophilic, lipophilic, and protein-bound analgesics/sedatives. These changes make
higher dosage necessary for achieving target analgesia and sedation. The dose titration and
weaning of these medications are done in a protocolized fashion like in any other critically ill
patient. Delirium is also very common in patients on ECMO and it requires close monitoring,
prevention, and aggressive management to improve outcomes.

REFERENCES
1. Barr J, Fraser GL, Puntillo K, et al.; American College of Critical Care Medicine. Clinical practice
guidelines for the management of pain, agitation, and delirium in adult patients in the intensive
care unit: executive summary. Am J Health Syst Pharm. 2013;70(1):53-8.
2. Brodie D, Bacchetta M. Extracorporeal membrane oxygenation for ARDS in adults. N Engl J Med.
2011;365(20):1905-14.
Chapter 35  Sedation and Pain Management on Extracorporeal Membrane Oxygenation 307
3. Shekar K, Fraser JF, Smith MT, et al. Pharmacokinetic changes in patients receiving extracorporeal
membrane oxygenation. J Crit Care. 2012;27(6):741.e9-18.
4. Wildschut ED, Ahsman MJ, Allegaert K, et al. Determinants of drug absorption in different ECMO
circuits. Intensive Care Med. 2010;36(12):2109-16.
5. Shekar K, Roberts JA, Mcdonald CI, et al. Sequestration of drugs in the circuit may lead to
therapeutic failure during extracorporeal membrane oxygenation. Crit Care. 2012;16(5):R194.
6. Tellor B, Shin N, Graetz TJ, et al. Ketamine infusion for patients receiving extracorporeal membrane
oxygenation support: a case series. F1000Res. 2015;4:16.
7. Riker RR, Shehabi Y, Bokesch PM, et al.; SEDCOM (Safety and Efficacy of Dexmedetomidine
Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of
critically ill patients: a randomized trial. JAMA. 2009;301(5):489-99.
8. Wagner D, Pasko D, Phillips K, et al. In vitro clearance of dexmedetomidine in extracorporeal
membrane oxygenation. Perfusion. 2013;28(1):40-6.
9. Kleiber N, Mathôt RA, Ahsman MJ, et al. Population pharmacokinetics of intravenous clonidine
for sedation during paediatric extracorporeal membrane oxygenation and continuous venovenous
hemofiltration. Br J Clin Pharmacol. 2017;83(6):1227-39.
10. Carson SS, Kress JP, Rodgers JE, et al. A randomized trial of intermittent lorazepam versus propofol
with daily interruption in mechanically ventilated patients. Crit Care Med. 2006;34(5):1326-32.
11. Lemaitre F, Hasni N, Leprince P, et al. Propofol, midazolam, vancomycin and cyclosporine
therapeutic drug monitoring in extracorporeal membrane oxygenation circuits primed with whole
human blood. Crit Care. 2015;19:40.
12. Mulla H, Lawson G, von Anrep C, et al. In vitro evaluation of sedative drug losses during
extracorporeal membrane oxygenation. Perfusion. 2000;15(1):21-6.
13. Arya VK, Kumar A, Thingnam SK. Propofol infusion into the pump during cardiopulmonary
bypass: is it safe and effective? J Cardiothorac Vasc Anesth. 2004;18(1):122-3.
14. Chanques G, Jaber S, Barbotte E, et al. Impact of systematic evaluation of pain and agitation in
an intensive care unit. Crit Care Med. 2006;34(6):1691-9.
15. Li D, Puntillo K, Miaskowski C. A review of objective pain measures for use with critical care adult
patients unable to self-report. J Pain. 2008;9(1):2-10.
16. Shekar K, Roberts JA, Ghassabian S, et al. Sedation during extracorporeal membrane oxygenation-
Why more is less. Anaesth Intensive Care. 2012;40(6):1067-9.
17. Shekar K, Roberts JA, Mullany DV, et al. Increased sedation requirements in patients receiving
extracorporeal membrane oxygenation for respiratory and cardiorespiratory failure. Anaesth
Intensive Care. 2012;40(4):648-55.
18. DeGrado JR, Hohlfelder B, Ritchie BM, et al. Evaluation of sedatives, analgesics, and neuromuscular
blocking agents in adults receiving extracorporeal membrane oxygenation. J Crit Care.2017;37:1-6.
19. Extracorporeal Life Support Organization (ELSO). General Guidelines for all ECLS Cases. ELSO
Guidel 2017. Extracorporeal Life Support Organization (ELSO); 2017. pp. 1-26.
20. Dzierba AL, Abrams D, Brodie D. Medicating patients during extracorporeal membrane
oxygenation: the evidence is building. Crit Care. 2017;21(1):66.
21. deBacker J, Tamberg E, Munshi L, et al. Sedation practice in extracorporeal membrane
oxygenation-treated patients with acute respiratory distress syndrome: a retrospective study.
ASAIO J. 2018;64(4):544-51.
22. Abrams D, Javidfar J, Farrand E, et al. Early mobilization of patients receiving extracorporeal
membrane oxygenation: a retrospective cohort study. Crit Care. 2014;18(1):R38.
CHAPTER 36
Transfusion Therapy during
Extracorporeal Membrane Oxygenation
Parshotam Lal Gautam, Suneet Kathuria, Shikha Gupta

INTRODUCTION
Patients on extracorporeal membrane oxygenation (ECMO) are subjected to transfusion of
large volumes of blood and blood component therapy. Extracorporeal life support (ECLS)
technology and applications have evolved from simple cardiopulmonary bypass (CPB)
machine, which was first successfully applied more than half a century ago by Dr John Gibbon
for cardiac surgery in operation room to a sophisticated ECMO in intensive care units (ICU).
These days ECMO is frequently being used in critical care practice as a support modality to
augment oxygenation, carbon dioxide removal, and cardiac output in acute hypoxemic
respiratory failure, cardiogenic shock, cardiac arrest [extracorporeal cardiopulmonary
resuscitation (CPR)], fulminant myocarditis, and many more potentially increasing indications
like medication overdose or poisoning, cardiac and lung transplant (as a bridge therapy to
transplant, intraoperative and postoperative ECMO support to primary graft failure, as a
hemodynamic support for major cardiac, vascular surgeries, and liver transplant, and as a
rescue strategy for acute perioperative cardiopulmonary failure, with good outcome. It may
be used as an adjunct to bridge patients with heart failure as they await transplantation or
placement of mechanical support devices such as a ventricular assist device (VAD). Its role is
also being tried in post-cardiac arrest deceased organ donors with promising results.1, 2
Extracorporeal circulation is fraught with problems related to acute inflammatory response
in form of hypercoagulation, bleeding, disease/drug/device-related thrombocytopenia and
other organ dysfunctions.3 Coagulopathy is one of the most frightful complications associated
with ECMO because of consumption and dilution of coagulation factors along with activation,
aggregation, and clumping of platelets in addition to its primary pathology, which often
is life-threatening and complex. Many a times, this leads to inappropriate blood and blood
product transfusions without any mortality benefit. Transfusions themselves predispose to
infection and thrombosis, and thus should be kept to a minimum. Taking into consideration,
the benefits and risks associated with blood transfusions in patients on ECMO, there is a need
for a thorough insight on standardization of blood and blood products transfusion triggers,
including age of stored packed red blood cells (PRBCs).
Chapter 36  Transfusion Therapy during Extracorporeal Membrane Oxygenation 309

NEED FOR BLOOD TRANSFUSION


List of indications for blood transfusion during extracorporeal support include restoring
oxygen carrying capacity, maintaining hemostatic balance, as ECMO circuit priming solution
and for treating hemorrhagic complications. It has reported that compromised organ functions
immediately before starting ECMO support, e.g. higher creatinine levels, lower prothrombin
time, and impaired platelet functions, etc., significantly increase the blood transfusion
requirement.4
The main purpose of red blood cell (RBC) transfusion during ECMO is to increase oxygen
delivery (DO2). Hence, maintaining a hemoglobin level within the normal range (12–14 g/dL)
during ECMO was previously suggested by extracorporeal life support organization (ELSO).1
But it has been seen that increasing DO2 does not always lead to increased oxygen uptake
(VO2).2,5 Despite adopting safe transfusion practices, various adverse effects like infections,
immune- and nonimmune-mediated reactions, etc. are known to be associated with blood
transfusions. Therefore, unless there is a strong indication of blood transfusion like severe
bleeding, the overall benefit of transfusions on oxygenation remains questionable. Like red
blood cell transfusion, platelet transfusion can also cause transfusion reactions with increased
risk of morbidity.6,7 Hence, based on these randomized controlled trials (RCTs)2-6 highlighting
the benefits of reducing transfusions, current guidelines recommend a restrictive transfusion
strategy in critically ill patients and the same concepts may be applied to patients on ECMO
as well. These days the incidence of hemolysis and bleeding complications has significantly
decreased, as the latest ECMO machines are more biocompatible, hence reducing the need
for blood transfusion.
Larger transfusion requirements in earlier times can be attributed to higher targets for
hemoglobin (>14 g/dL) and anticoagulation levels (ACT: 180–220 seconds) and use of blood
as priming solution for ECMO machines.8 Modern ECMO circuits are more biocompatible,
heparin-coated, shorter in length with small oxygenators, and the use of crystalloids for
priming leading to a decreased incidence of bleeding complications and the need for blood
transfusion.

STORAGE LIFE OF RED BLOOD CELLS


Packed red blood cells can be safely refrigerated for about 42 days and platelet concentrates
can be stored for 5 days at 20–24°C. Stored RBCs undergo undesirable structural and metabolic
changes in form of increased lactate levels, pH decreased to less than 6.5, decreased adenosine
triphosphate and nicotinamide adenine dinucleotide levels, 2,3-diphosphoglycerate
(DPG) depletion, sodium and potassium exchange impairment, increased oxidative stress
(hemoglobin is oxidized to methemoglobin), RBC cytoskeletal membrane disruption, and
formation of microvesicles.6 Due to depletion of 2,3-DPG and adenosine triphosphate (ATP),
the oxygen binding capacity in stored RBCs is reduced.2 Structural changes in stored RBCs lead
to loss of deformability and increased osmotic fragility, causing increase in free hemoglobin
levels. Hence, old stored PRBCs transfusion poses increased risk of thrombosis and infection.9,10
In patients undergoing cardiac surgery, transfusion of aged PRBCs is responsible for decreased
survival.11
310 Section 2  Extracorporeal Membrane Oxygenation

On the basis of the American Association of Blood Banks (AABB) transfusion guidelines,
patients of all ages requiring blood transfusion should be given red cell units as per standard
issue policy (i.e. first in first out, within approved shelf-life) rather than preferential fresh
RBC units (<10 days storage life).12 Heddle and colleagues13 compared mortality rates among
patients receiving short-duration (13.0 days) and long-duration (23.6 days) stored blood
transfusions. There was no significant difference in mortality amongst those who received
transfusion with the freshest available blood and the oldest available blood.

IMPACT OF RBC TRANSFUSION ON OXYGEN


In order to increase oxygen delivery (DO2), decision to start RBCs transfusions were based on
“10/30 rule” previously (hemoglobin > 10 g/dL and hematocrit > 30%).14 It was presumed that
RBC transfusion in patients on ECMO increases DO2.11 However, current RCTs demonstrate
that over a wide range, oxygen uptake (VO2) is independent of DO2. Whenever there is
a decrease in DO2 levels, the oxygen extraction (VO2/DO2) increases as a compensatory
mechanism.5 Therefore, when there is acute bleeding or hypoxemia, VO2 remains stable until
DO2 falls below a critical level and hence, RBC transfusion is rarely required unless severe
anemia is associated with hemorrhagic shock. Therefore, indication for blood transfusion
should not be based on absolute hemoglobin level rather we must focus on volume status
of the patients, cardiopulmonary functions, and the duration and severity of anemia. The
1988 National Institutes of Health Consensus Conference on Perioperative Red Blood Cell
Transfusions also suggested that no single criterion should be used as an indication for red
cell component therapy, and that multiple factors related to the patient’s clinical status and
oxygen delivery should be considered.15 Hence, a parameter reflecting VO2/DO2 may be used
as an ideal transfusion trigger.5
A study by Schmidt M et al. on patients who received venovenous ECMO for acute
respiratory distress syndrome (ARDS) reported that transfusions increased oxygen content,
oxygen delivery, and allowed for a reduction in ECMO blood flow rate.16 They emphasized that
any potential benefit of transfusion must be weighed against the risk because multiple clinical
studies demonstrate an association between transfusions and worsened outcomes, including
poor wound healing of transfusion-related acute lung injury, volume overload, and increased
death.

TRANSFUSION TRIGGER IN CRITICALLY ILL PATIENTS


Higher number of transfusions are associated with increased ICU mortality. Liberal strategies
that propagate transfusion to nearly normal hemoglobin levels, have reported increased
morbidity and mortality as compared to conservative approaches that accept a moderate
degree of anemia (up to 7.0 g/dL hemoglobin).17-20
American Association of Blood Banks Transfusion Guidelines (2016) recommend
restricting blood transfusion, if hemoglobin level is more than 7 g/dL in hemodynamically
stable hospitalized adult patients and including critically ill patients, whereas hemoglobin
level of 8 g/dL is recommended for patients undergoing orthopedic surgery, cardiac surgery,
and those with preexisting cardiovascular disease. The AABB suggests that transfusion
Chapter 36  Transfusion Therapy during Extracorporeal Membrane Oxygenation 311
decisions should not solely be based on hemoglobin concentration but should also be guided
by symptoms.12
Other investigators like Canadian Critical Care Trial Group,10 Transfusion Trigger Trial for
Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair
(FOCUS), CRIT study, and Transfusion Requirements in Septic Shock (TRISS) trial also support
the transfusion trigger of 7 g/dL.18-21 Holst et al. in a meta-analysis showed that restrictive
transfusion strategies were associated with a reduction in the number of RBCs transfused and
percent of patients transfused, without increasing mortality or ischemic events.22
Transfusion Indication Threshold Reduction (TITRe2) investigators have reported data
against restrictive transfusion strategies.23 A restrictive transfusion threshold after cardiac surgery
was not found to be superior to a liberal threshold with respect to healthcare costs or morbidity.
Serious postoperative complications occurred in 35.7% of participants in the restrictive threshold
group and 34.2% of participants in the liberal threshold group and more deaths were reported in
restrictive threshold group (4.2%) than in the liberal threshold group (2.6%).
Taken together, restrictive transfusion strategies are preferred over liberal strategies in
critically ill patients, and a low hemoglobin target (i.e. 7 g/dL) is recommended for transfusion
threshold. As liberal blood transfusions strategies have failed to improve oxygen delivery, the
practice of restrictive transfusions may safely be extended to patients receiving ECMO as an
interim opinion till definite evidence-based guidelines are available.

CURRENT TRANSFUSION PRACTICE IN ECMO PATIENTS


The guidelines by the ELSO recommend to maintain hemoglobin levels between 12 g/dL and
14 g/dL, and platelet counts > 75,000/mm3.1 These guidelines also advise to maintain SaO2
above 95% and SvO2 above 75%, in patients receiving venoarterial (VA) ECMO, and SaO2 above
80% and SvO2 above 70% in patients on venovenous (VV) ECMO.
Depending upon disease characteristics, comorbidities and age of the patients, the
transfusion requirements in patients on ECMO differ. Adult patients receiving ECMO require a
greater number of transfusions than neonates or children because of the larger body size and
requirement of ECMO for a longer duration amongst adults.14
Chevuru et al. reported that neonates receiving ECMO because of sepsis/meconium
aspiration required more platelet transfusions (1.9 units/day) than neonates requiring ECMO
because of other indications.24 Also, the number of platelet transfusions required per day has
a significant direct relationship with the type of ECMO therapy used. VV ECMO patients have
the lowest transfusion requirement. Pediatric patients receiving ECMO therapy because of
cardiac disease or congenital diaphragmatic hernia require a greater number of transfusions
than those requiring ECMO therapy because of pulmonary cause.25
In a study by Omar et al. on adult ECMO patients reported that 5 units of RBCs and 9 units
of platelets were transfused per day (ECMO duration: 5 days; 82% cases on VA ECMO).26 Ang et
al. in their study on 41 adult patients on ECMO (83% patients received VA ECMO) also reported
that 2 units of packed RBCs and 3 units of platelets transfusions were given daily.14 They also
reported that the lowest levels of hemoglobin and platelet were observed on 3rd day of ECMO
and >10 packed RBC units were required in 55% of patients.
312 Section 2  Extracorporeal Membrane Oxygenation

Lesser number of transfusions was required in patients on VV ECMO for respiratory


failure as compared to cardiac failure patients receiving VA ECMO. In 2009, H1N1 pandemic
period, an average of 0.75 unit/day RBCs were transfused in ARDS patients on VV ECMO as
reported by the Australia and New Zealand Extracorporeal Membrane Organization Influenza
investigators.27 Italian ECMO network study on ARDS patients with influenza reported 1500
mL of RBCs transfusion requirement per patient (0.6 units/day) during 10 ECMO days.28

RESTRICTED TRANSFUSION STRATEGIES IN ECMO PATIENTS


There is substantial evidence from current literature to favor restrictive strategy. Liberal
transfusion strategies are not only without much of benefit for the patients on ECMO, rather
they have the potential to harm, whereas restrictive transfusion strategies are considered to be
safe in patients on ECMO.
Smith et al. highlighted that infants or children undergoing cardiac ECMO require higher
transfusion volume than those on ECPR and the nonsurvivors received more transfusions than
survivors.29 Omar et al. also have concluded in their study that the volume of transfused RBCs
and platelets was higher in nonsurvivors compared to survivors.21
Voelker MT et al. in their study on 18 patients with severe ARDS on ECMO, maintained
a hemoglobin concentration between 7.0 g/dL and 9.0 g/dL (transfusion trigger-hemoglobin
<7.0 g/dL). Overall mortality in their study was 38.9%, and it was observed that nonsurvivors
received higher transfusion volume (1.97 units/day) than survivors (0.96 units/day).30
Blood conservation strategy by Agerstrand et al. employed transfusion trigger of hemoglobin
<7.0 g/dL; an activated partial thromboplastin time (APTT) levels between 40 seconds and
60 seconds, and the use of autotransfusion techniques in 38 ARDS patients on ECMO.31 The
transfusion rate in their series was 63.2% and the survival rate was 73.7%. In order to maintain
SpO2 > 92%, they increased the ECMO flow rate, rather than transfusing RBCs and on average,
1 PRBC unit/patient was transfused during ECMO (0.11 units/day/patient). They also noted
that rate of thrombosis and bleeding complications were unremarkable. The higher volume of
blood transfusion is associated with higher mortality, rather than absolute hemoglobin levels.31
Christine M Cahill et al., in their recent study on a standard transfusion protocol in cardiac
patients on VA ECMO, found improved clinical outcome along with decreased need for blood
component transfusion.32 They formulated separate transfusion protocols for transfusion
triggers in bleeding and nonbleeding patients. In patients on ECMO who were not bleeding,
the targets set for PRBC transfusion if hemoglobin < 8 g/dL, for platelet transfusion if platelet
count < 60 × 109/L, and for fresh-frozen plasma (FFP) transfusion if international normalized
ratio (INR) > 1.7. Apart from decreased blood component utilization and costs, with adoption
of standard protocol, there was a significant improvement in terms of survival (33% in the pre-
protocol era vs 63% in post-ECMO transfusion protocol era). Thirty-day survival post-ECMO
was achieved in 9 of 10 pre-protocol patients and 19 of 19 of the post-protocol cohort. They
emphasized each transfusion decision ideally should be made in the context of clinical factors
and hemodynamic stability rather than solely relying on laboratory hemoglobin values. Final
decision to start transfusion should be based on risks and benefit analysis individualized for
each patient and for each transfusion.
Chapter 36  Transfusion Therapy during Extracorporeal Membrane Oxygenation 313

OTHER STRATEGIES FOR REDUCING TRANSFUSION VOLUME


Use of autotransfusion in ECMO helps in reducing RBC transfusion volume. Autologous
transfusion lowers humoral immune response, infection risk, and shorter length of hospital
stay.33 At the time of ECMO decannulation, autotransfusion helps in returning most of circuit
blood back to the patient, thus leading to avoidance of PRBC transfusions near the time of
decannulation.
A low-dose anticoagulation protocol also appears to be safe, effective, and reduces bleeding
complications and hence decreases the need for PRBC transfusions. As compared to APTT-
guided heparin anticoagulation protocol, patients managed with an activated clotting time
(ACT)-guided protocol receive more blood transfusion, which points to greater bleeding in
patients on VA ECMO being managed with ACT.34
Extracorporeal membrane oxygenation duration should be minimized, as the duration
of ECMO is associated with volume of transfusion and a tendency toward decreased platelet
count.14,17,35 Minimizing daily sampling volume helps in minimizing investigational anemia
and reducing transfusion requirement.31,17 Adoption of standardized transfusion protocol and
educating medical personnel also helps in transfusion volume.31,17

SUMMARY
As of today, most of clinical evidence on transfusion strategies is available from studies in
critically ill patients and direct evidence from ECMO studies is limited. Recent improvements
in ECMO technology with better circuits have decreased machine-induced damage and blood
transfusion requirement. Current data support a restrictive transfusion strategy for ECMO
patients. Keeping a low transfusion trigger of hemoglobin < 7.0 g/dL, anticoagulation target of
APTT levels between 40 seconds and 60 seconds, minimizing phlebotomies, and performance
of autotransfusion during decannulation, is beneficial in decreasing transfusion requirements.
Reducing ECMO duration is also beneficial in decreasing the need for transfusions. Rather
than focusing exclusively on absolute hemoglobin concentration, as a transfusion trigger, we
should also take patient’s clinical condition into consideration.

REFERENCES
1. Extracorporeal Life Support Organization (ELSO). ELSO Guidelines. Ann Arbor: ELSO; 2016.
[online] Available from: https://www.elso.org/Resources/Guidelines.aspx. [Last accessed October,
2019].
2. Makdisi G, Wang IW. Extra corporeal membrane oxygenation (ECMO) review of a lifesaving
technology. J Thorac Dis. 2015;7(7):E166-76.
3. Holst LB. Benefits and harms of red blood cell transfusions in patients with septic shock in the
intensive care unit. Dan Med J. 2016;63(2). pii: B5209.
4. Tauber H, Streif W, Fritz J, et al. Predicting transfusion requirements during extracorporeal
membrane oxygenation. J Cardiothorac Vasc Anesth. 2016;30(3):692-701.
5. Roberson RS, Bennett-Guerrero E. Impact of red blood cell transfusion on global and regional
measures of oxygenation. Mt Sinai J Med. 2012;79(1):66-74.
6. Orlov D, Karkouti K. The pathophysiology and consequences of red blood cell storage. Anaesthesia.
2015;70 (Suppl 1):29-37, e9-12.
314 Section 2  Extracorporeal Membrane Oxygenation

7. Kiefel V. Reactions induced by platelet transfusions. Transfus Med Hemother. 2008;35(5):354-8.


8. Butch SH, Knafl P, Oberman HA, et al. Blood utilization in adult patients undergoing extracorporeal
membrane oxygenated therapy. Transfusion. 1996;36(1):61-3.
9. Lelubre C, Vincent JL. Red blood cell transfusion in the critically ill patient. Ann Intensive Care.
2011;1:43.
10. Tinmouth A, Fergusson D, Yee IC, et al.; ABLE Investigators; Canadian Critical Care Trials Group.
Clinical consequences of red cell storage in the critically ill. Transfusion. 2006;46(11):2014-27.
11. Koch CG, Li L, Sessler DI, et al. Duration of red-cell storage and complications after cardiac
surgery. N Engl J Med. 2008;358(12):1229-39.
12. Carson JL, Guyatt G, Heddle NM, et al. Clinical Practice Guidelines from the AABB: red blood cell
transfusion thresholds and storage. JAMA. 2016; 316(19):2025-35.
13. Heddle NM, Cook RJ, Arnold DM, et al. Effect of short-term vs. long-term blood storage on
mortality after transfusion. N Engl J Med. 2016;375(20):1937-45.
14. Ang AL, Teo D, Lim CH, et al. Blood transfusion requirements and independent predictors of
increased transfusion requirements among adult patients on extracorporeal membrane oxygenation
-- a single centre experience. Vox Sang. 2009;96(1):34-43.
15. Consensus conference. Perioperative red blood cell transfusion. JAMA. 1988; 260(18):2700-3.
16. Schmidt M, Tachon G, Devilliers C, et al. Blood oxygenation and decarboxylation determinants
during venovenous ECMO for respiratory failure in adults. Intensive Care Med. 2013;39(5):838-46.
17. Rosenberg EM, Chambers LA, Gunter JM, et al. A program to limit donor exposures to neonates
undergoing extracorporeal membrane oxygenation. Pediatrics. 1994;94(3):341-6.
18. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT study: anemia and blood transfusion in the
critically ill--current clinical practice in the United States. Crit Care Med. 2004;32(1):39-52.
19. Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of
transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators,
Canadian Critical Care Trials Group. N Engl J Med. 1999;340(6):409-17.
20. Vincent JL, Baron JF, Reinhart K, et al.; ABC (Anemia and Blood Transfusion in Critical Care)
Investigators. Anemia and blood transfusion in critically ill patients. JAMA. 2002;288(12):1499-507.
21. Carson JL, Terrin ML, Noveck H, et al.; FOCUS Investigators. Liberal or restrictive transfusion in
high-risk patients after hip surgery. N Engl J Med. 2011;365(26):2453-62.
22. Holst LB, Petersen MW, Haase N, et al. Restrictive versus liberal transfusion strategy for red blood
cell transfusion: systematic review of randomised trials with meta-analysis and trial sequential
analysis. BMJ. 2015;350:h1354.
23. Murphy GJ, Pike K, Rogers CA, et al.; TITRe2 Investigators: Liberal or restrictive transfusion after
cardiac surgery. N Engl J Med. 2015;372(11):997-1008.
24. Chevuru SC, Sola MC, Theriaque DW, et al.; Florida Collaborative Neonatology Research Group.
Multicenter analysis of platelet transfusion usage among neonates on extracorporeal membrane
oxygenation. Pediatrics. 2002;109(6):e89.
25. Henríquez-Henríquez M, Kattan J, Chang M, et al. Blood component usage during extracorporeal
membrane oxygenation: experience in 98 patients at a Latin-American tertiary hospital. Int J Artif
Organs. 2014;37(3):233-40.
26. Omar HR, Mirsaeidi M, Socias S, et al. Plasma free haemoglobin is an independent predictor
of mortality among patients on extracorporeal membrane oxygenation support. PLoS One.
2015;10(4):e0124034.
27. Davies A, Jones D, Bailey M, et al.; Australia and New Zealand Extracorporeal Membrane
Oxygenation (ANZ ECMO) Influenza Investigators. Extracorporeal membrane oxygenation for 2009
influenza A(H1N1) acute respiratory distress syndrome. JAMA. 2009;302(17):1888-95.
28. Patroniti N, Zangrillo A, Pappalardo F, et al. The Italian ECMO network experience during the 2009
influenza A(H1N1) pandemic: preparation for severe respiratory emergency outbreaks. Intensive
Care Med. 2011;37(9):1447-57.
Chapter 36  Transfusion Therapy during Extracorporeal Membrane Oxygenation 315
29. Smith A, Hardison D, Bridges B, et al. Red blood cell transfusion volume and mortality among
patients receiving extracorporeal membrane oxygenation. Perfusion. 2013;28(1):54-60.
30. Voelker MT, Busch T, Bercker S, et al. Restrictive transfusion practice during extracorporeal
membrane oxygenation therapy for severe acute respiratory distress syndrome. Artif Organs.
2015;39(4):374-8.
31. Agerstrand CL, Burkart KM, Abrams DC, et al. Blood conservation in extracorporeal membrane
oxygenation for acute respiratory distress syndrome. Ann Thorac Surg. 2015;99(2):590-5.
32. Cahill CM, Blumberg N, Schmidt AE, et al. Implementation of a standardized transfusion protocol
for cardiac patients treated with venoarterial extracorporeal membrane oxygenation is associated
with decreased blood component utilization and may improve clinical outcome. Anesth Analg.
2018;126(4):1262-7.
33. Tolksdorf B, Schmeck J, Osika A, et al. Autotransfusion during extracorporeal membrane
oxygenation. Int J Artif Organs. 2000;23(12):840-4.
34. Mazzeffi MA, Tanaka K, Roberts A, et al. Bleeding, thrombosis, and transfusion with two
heparin anticoagulation protocols in venoarterial ECMO patients. J Cardiothorac Vasc Anesth.
2019;33(5):1216-20.
35. Ferraris VA, Davenport DL, Saha SP, et al. Intraoperative transfusion of small amounts of blood
heralds worse postoperative outcome in patients having noncardiac thoracic operations. Ann
Thorac Surg. 2011;91(6):1674-80.
CHAPTER 37
Extracorporeal Membrane
Oxygenation Complications
Charudatt Vaity, Jitendra Chaudhari, Rahul Pandit

INTRODUCTION
Extracorporeal membrane oxygenation (ECMO) is modality used to support failing respiratory
and cardiovascular system. The concept of ECMO initially was developed in 1950s by John
Gibbin who used this in prolonged operation on cardiopulmonary bypass. Gradually as
technology evolved, people started using ECMO to support patients of “shock lung syndrome”,
“adult capillary leak syndrome”, and cardiac failures in 1960s and 1970s.1 Randomized
controlled trials conducted on adult patients with severe respiratory distress in 1979 showed
around 90% mortality.2 ECMO usage was limited to mostly neonates and pediatric patients
for next 30 years. During 2009 pandemic of H1N1, ECMO was successfully used to treat acute
respiratory distress syndrome (ARDS) in many patients and this has led to resurgence in the
interest of ECMO therapy.1,3
Extracorporeal membrane oxygenation is an extreme procedure, used for life-threatening
respiratory and cardiac failure.4 Advances in providing ECMO has led to improved survival and
opportunity for end-stage patients to have a bridge to definitive therapy. ECMO, though, is not
without risks. Most common complication has been bleeding from cannula as well as surgical site
(28–46%). Over time, oxygenator failure and pump-related complications have come down from
8–10% to 0.8%.5

EXTRACORPOREAL MEMBRANE OXYGENATION COMPLICATIONS


We can classify the ECMO-related complications as follows:
■ Vascular
■ Bleeding
■ Neurological
■ Technical
■ Infection.

Vascular
Vascular complications are the leading cause of mortality in patients undergoing ECMO.
Survival to discharge rate for patients on ECMO was as low as 18% in one of the studies.6 Most
Chapter 37  Extracorporeal Membrane Oxygenation Complications 317
common complication of ECMO is limb ischemia which is reported in 10–70% of patients
undergoing venoarterial (VA) ECMO.7-9 Dissection of the femoral artery, pseudoaneurysm
formation, retroperitoneal bleed, and infection of the groin are some other vascular
complications.

Limb Ischemia
During peripheral VA ECMO, insertion of large-bore cannulas in the femoral artery along
with ongoing hemodynamic instability puts the limb at risk for ischemia. Common femoral
artery is smaller in women and younger patients.7 In these patients, placing large-bore
cannulas (>20 Fr) increases the risk of vascular compromise.10 Clinical presentation can vary
from pain, pallor, calf swelling to gangrene. Vascular insufficiency can be diagnosed by use
of Doppler ultrasound. Near-infrared spectroscopy (NIRS) has also shown to be useful to
identify limb ischemia. Baseline SpO2 of more than 94% is a good indicator of perfusion.
Incidence of limb ischemia can be reduced by placing a distal perfusion catheter (DPC) to
provide limb perfusion.7,9,11 Compartment syndrome can be identified clinically if the calf
is tense with pain and paresthesia. Prompt decompression with fasciotomies is required
to salvage the limb. Postfasciotomies, adjustment of anticoagulation may be required to
prevent bleeding.

Vascular Injury
Dissection, pseudoaneurysm, and retroperitoneal bleeding can occur during the initial
placement or during the time of removal of cannulas in 7–14% patients.12 Most arterial dis-
sections are asymptomatic but can sometimes lead to arterial occlusion. Symptomatic arterial
dissections may need placement of stent or relocation of the cannula. Pseudoaneurysms
present as painful swelling in the groin, which is pulsatile on examination. This can be
confirmed on ultrasound. Ultrasound also helps to identify the anatomy and describe
whether the pseudoaneurysm is wide or narrow necked. Narrow-neck pseudoaneurysms
can be managed by injecting thrombin whilst the large-neck pseudoaneurysms will need
surgical intervention. As patients on ECMO are usually on systemic anticoagulation, they have
tendencies to develop internal hematomas even with minor vascular injuries. Unexplained
drop in hematocrit with hemodynamic compromise should prompt to look for any vascular
injury. This can be confirmed on imaging. Patients can be managed either conservatively by
correcting the anticoagulation and transfusions. If conservative methods do not work, then
endovascular intervention and embolization may be required. Very rarely, open surgical
intervention may be required.

Late Vascular Complication


Late vascular complication can develop at the previous arterial cannulation site. Technical
problems during explantation and history of peripheral vascular disease are independent
predictors of development of late vascular complications.11 Late vascular complication is
vascular stenosis at former cannulation site. This complication will mostly need surgical
revascularization in form of either percutaneous transluminal angioplasty, femorofemoral
crossover bypass, iliofemoral bypass, or thromboendarterectomy. As a preventive strategy to
318 Section 2  Extracorporeal Membrane Oxygenation

avoid late complication, if there is a technical problem during explantation, autologous patch
plastic can be performed at the time of explantation. Choosing alternate cannulation sites
such as central (Vene cava/Aortic) cannulation and cannulation through axillary/subclavian
artery using coated vascular prosthesis.13,14

Bleeding
Contact activation of coagulation and clot formation can occur in the first few hours after
initiating ECMO. Bleeding and thrombosis are very common on ECMO. In vivo thrombosis is
not very common but clot formation in circuit is possible despite adequate anticoagulation.
These patients need systemic anticoagulation; most commonly used is heparin. The incidence
of bleeding ranges between 10% and 30%.5
The most common site of bleeding is from cannula insertion site and other surgical sites.
Bleeding can also occur from airway and gastrointestinal (GI) tract.15 Intracranial bleed
is the most dreaded complication and can be rapidly fatal. Etiology for bleeding can be
overanticoagulation, coagulopathy, platelet dysfunction, or thrombocytopenia and acquired
von Willebrand syndrome (AVWS).16

Overanticoagulation
Heparin is most commonly used systemic anticoagulation. The target activated clotting
time (ACT) is between 210 seconds and 230 seconds. Anticoagulation action of heparin is
anti-Xa and anti-IIa, involving antithrombin, heparin cofactor II, and tissue factor pathway
inhibitor (TFPI). Heparin overdose is one of the common causes of bleeding in patients on
ECMO.

Coagulopathy
Dilutional coagulopathy and thrombocytopenia are common immediately after activation of
ECMO, if ECMO circuit is primed with saline or red cells only. Other cause for coagulopathy is
consumption because of constant thrombin formation leading to low fibrinogen levels due to
contact with extracorporeal surface.

Thrombocytopenia
Constant shear force caused by pump is important reason for thrombocytopenia. Also, there
may be functional defect in platelet function. Reduced levels of glycoprotein Ibα and
glycoprotein VI may be responsible for reduced platelet function. Other cause of thrombo-
cytopenia may be heparin-induced thrombotic thrombocytopenia (HITT). If HITT is
suspected, it is advisable to use alternative anticoagulation such as argatroban or bivalirudin.

Hyperfibrinolysis
During ECMO, there is excessive release of tissue plasminogen activator (tPA) from endothelial
cells, which causes activation of fibrinolytic system.16 Use of antifibrinolytic agents did show
reduction in surgical bleeding.
Chapter 37  Extracorporeal Membrane Oxygenation Complications 319

Acquired von Willebrand Syndrome


Acquired von Willebrand syndrome is seen in most patients on ECMO, but it is highly under
recognized cause for complications. Loss of large multimers of von Willebrand factor (VWF) is
caused by high shear forces associated with ECMO. Diagnosis of AVWS is based on decreased
VWF activity to VWF antigen ratio and decreased large multimer bands of VWF multimer
study.
Treatment for AVWS is cryoprecipitate or VWF transfusion. There is continuous
high shear force in patients on ECMO or ventricular assist device (VAD); so effects of
cryoprecipitate or VWF transfusion is temporary.5,17 Cryoprecipitate contains VWF as
well as factor VIII and fibrinogen. If levels of these factors are already raised in patients,
cryoprecipitate transfusion may precipitate thrombus formation. Also, VWF concentrate
contains large concentration of factor VIII. If patient already has increased levels of factor
VIII, VWF concentrate transfusion may cause increased thrombosis. In United States
market, recombinant VWF is available. This is recommended treatment for treatment of
AVWS in patients with elevated factor VIII.16

Hemolysis
Hemolysis releases free hemoglobin in plasma; this enhances in vitro VWF-mediated platelet
adhesion. This augments microthrombi formation on fibrinogen, fibrin, and extracellular
matrix at high shear stress. Once clot formation starts in ECMO circuit, they continue to
consume coagulation factors as well as platelets and leads to consumption coagulopathy.5

Neurological Complications
Neurological complications of ECMO are associated with increased mortality and morbidity
and ranges between subtle cognitive impairment and brain death.
Neurological damage can include seizure, stroke, intracranial hemorrhage, ischemic
encephalopathy, and brain death.18 Paraplegia and spinal cord infarct are another rare
complications described in one case study.19 Neurological complications are underestimated
because of lack of diagnostic imaging in critically ill patients, limited reporting in registries,
and lack of standardized reporting. Recent data from extracorporeal life support organization
(ELSO) shows incidence of neurological complications to be around 13%.17,18,20 Stroke (4%)
and intracranial bleed (ICH) (2%) are important contributors for increased mortality and
morbidity. ICH is particularly associated with poor outcome, with mortality rates as high as
80–90%.18
The neurological injury can occur pre-ECMO due to severe hypo-/hypertension (deranged
cerebral autoregulation), hypo-/hyperglycemia, pyrexia, metabolic acidosis, electrolyte
disturbance, and cerebral emboli.21 On ECMO, cerebral infarction can occur because of
solid and/or gaseous microemboli and thrombi formed in cannula.22 In patient with severe
hypercarbia, sudden reduction in carbon dioxide can cause cerebral vasoconstriction and may
lead to cerebral infarction. Possible risk factors for neurological injury specifically in VA ECMO
setting are “loss pulsatile flow” and “differential hypoxia”.20
320 Section 2  Extracorporeal Membrane Oxygenation

Cognitive impairment, prolonged hospitalizations, increased healthcare costs, higher


rates of discharge to a long-term care facility, and greater long-term mortality are reasons
for poorer outcomes in patients with acute ischemic stroke or intracranial hemorrhage.23
Diagnosis of neurological event may be difficult because of deep sedation and difficulty in
neurological imaging in patients on ECMO. Other methods such as seizure activities, abnormal
electroencephalogram, and somatosensory-evoked potential are helpful in diagnosing
neurological complications. Brain biomarkers such as S100β and neuron-specific enolase
(NSE) can be useful to detect neuronal injury and may help in assessing the usefulness of
interventions.24

Technical Complications
Technical complications are known risks in ECMO. Over the years, ECMO circuitry, pump,
and oxygenator technology have improved considerably to provide safer perfusion for longer
time.
Technical complications can be classified into two categories:
1. Technical complications requiring acute exchange of the system
2. Technical complications requiring planned exchange of system.

Technical Complications Requiring Acute Exchange of System


Mechanical failure: Mechanical failure is leakage at membrane oxygenator (MO), connectors, or
pump head. Failure of blood pumps can be due to electrical failure requiring to use hand crank
to bridge pump drive till the exchange of the system takes place. Material defect and imbalance
of the pump head can be some other causes of acute mechanical failure. Intense pump head
movement can cause partial rupture of the cannula requiring urgent clamping to avoid further
sequelae.25
Acute clot: Acute clot formation can occur at pump head or MO.26 Pump head thrombosis
can be identified by sudden change sound from pump head with vibrations in the circuit,
progressive pump-induced hemolysis. Hemolysis can be identified by high free hemoglobin
and D-dimers. Now with free access to smartphones which can do slow-motion recording, this
can be used to visualize the actual thrombus.27

Technical Complications Requiring Planned Exchange of System


Worsening gas exchange capability of the system: During prolonged ECMO, cellular, fibrin, and
thrombotic deposits promote the progression of clot formation within the circuit.28 This leads
to worsening of gas exchange capability of MO requiring planned exchange.
Worsening gas exchange capability of the system can be identified by serially monitoring
the blood gas at the outlet of the MO (postMO). More than 50% decrease in the partial pressure
of O2 compared to the initial value and increase in the partial pressure of CO2 over 40 mm Hg at
high sweep flow (≥10 L/min) at outlet (postMO) indicates worsening gas exchange and should
prompt planned exchange of the system.25
Chapter 37  Extracorporeal Membrane Oxygenation Complications 321
Oxygenation failure: With worsening gas exchange capabilities and along with severe
VQ (ventilation Perfusion) mismatch can lead to severe oxygenation failure especially in
venovenous ECMO. This is often difficult to correct and consideration may be necessary to
change the circuit.
Device-induced coagulopathy: Unexplained increase in levels of D-dimer, decrease in
fibrinogen concentration and decrease in platelets are markers for device-induced
coagulopathy. There is no other cause for this coagulation disorder and the markers
subsequently improve after exchange of the system. Thus, until exchange of the system is done,
device-induce coagulopathy is a presumptive diagnosis.
Suspected infection of the circuit: If there are clinical observations along with positive blood
cultures and raised inflammatory markers [C-reactive protein (CRP), procalcitonin (PCT)-q,
and leukocytosis) without any obvious focus for infection then it is possible that the ECMO
circuit is the source. The inflammatory markers and constitutional symptoms tend to improve
after the system is exchanged.25

Infections
Patients on ECMO have higher infectious risk in comparison to other critically ill patients.
The prevalence of infections in adults on ECMO is as high as 21% as per the review
performed on ESLO registry.29,30 Bloodstream infections range from 3% to 18% followed
by lower respiratory infections at 24.4 episodes/100 ECMO days.31-33 The risk of death, for
patients with nosocomial infections on ECMO is 38–63%.29,30 Precannulation sequential
organ failure assessment (SOFA) score is an independent risk factor for developing
infectious complications. Patients on VA ECMO have more tendency to develop infectious
complications compared to venovenous (VV) ECMO.33 There is also significant association
between duration of ECMO and occurrence of infectious complications.32,34 Though there
is no evidence for use of prophylactic antibiotics during ECMO, it remains a common
practice.35,36

ECMO-induced Hypertension
Hypertension in V-V ECMO is commonly seen in pediatric age group. However, it is reported
in adults as well. It is related to the increase in plasma renin activity (PRA). Hypertension can
contribute to increase risk of bleeding, especially intracranial hemorrhage. It can be controlled
with short-acting ACE inhibitors like enalapril.37

SUMMARY
Extracorporeal membrane oxygenation has over the recent years developed in an important
tool to improve survival in patients with cardiorespiratory failure but there is significant
morbidity associated with this intervention. ECMO complications are quite varied from
bleeding to thrombosis and it is prudent to be aware of these complications before initiating
ECMO. Careful patient selection and timing the initiation of ECMO is important to minimize
the incidence of the complications and will improve survivability.
322 Section 2  Extracorporeal Membrane Oxygenation

REFERENCES
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ill adults in the emergency department: history, current applications, and future directions. Crit
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6. Tanaka D, Hirose H, Cavarocchi N, et al. The impact of vascular complications on survival of
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1729-34.
7. Foley PJ, Morris RJ, Woo EY, et al. Limb ischemia during femoral cannulation for cardiopulmonary
support. J Vasc Surg. 2010;52(4):850-3.
8. Aziz F, Brehm CE, El-Banyosy A, et al. Arterial complications in patients undergoing extracorporeal
membrane oxygenation via femoral cannulation. Ann Vasc Surg. 2014;28(1):178-83.
9. Bisdas T, Beutel G, Warnecke G, et al. Vascular complications in patients undergoing femoral
cannulation for extracorporeal membrane oxygenation support. Ann Thorac Surg. 2011;92(2):
626-31.
10. Lamb KM, DiMuzio PJ, Johnson A, et al. Arterial protocol including prophylactic distal perfusion
catheter decreases limb ischemia complications in patients undergoing extracorporeal membrane
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11. Zimpfer D, Heinisch B, Czerny M, et al. Late vascular complications after extracorporeal membrane
oxygenation support. Ann Thorac Surg. 2006;81(3):892-5.
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15. Aubron C, DePuydt J, Belon F, et al. Predictive factors of bleeding events in adults undergoing
extracorporeal membrane oxygenation. Ann Intensive Care. 2016;6(1):97.
16. Thomas J, Kostousov V, Teruya J. Bleeding and thrombotic complications in the use of extracorporeal
membrane oxygenation. Semin Thromb Hemost. 2018;44(1):20-9.
17. Cheng R, Hachamovitch R, Kittleson M, et al. Complications of extracorporeal membrane
oxygenation for treatment of cardiogenic shock and cardiac arrest: a meta-analysis of 1,866 adult
patients. Ann Thorac Surg. 2014;97(2):610-6.
18. Nasr DM, Rabinstein AA. Neurologic complications of extracorporeal membrane oxygenation. J
Clin Neurol. 2015;11(4):383-9.
19. Samadi B, Nguyen D, Rudham S, et al. Spinal cord infarct during concomitant circulatory support
with intra-aortic balloon pump and veno-arterial extracorporeal membrane oxygenation. Crit Care
Med. 2016;44(2):e101-5.
Chapter 37  Extracorporeal Membrane Oxygenation Complications 323
20. Xie A, Jayewardene ID, Dinale A, et al. Cerebral hypoxia during venoarterial extracorporeal
membrane oxygenation: an in-vitro study. J Heart Lung Transplant. 2015;34(Suppl 4):S196-7
21. Mateen FJ, Muralidharan R, Shinohara RT, et al. Neurological injury in adults treated with
extracorporeal membrane oxygenation. Arch Neurol. 2011;68(12):1543-9.
22. Risnes I, Wagner K, Nome T, et al. Cerebral outcome in adult patients treated with extracorporeal
membrane oxygenation. Ann Thorac Surg. 2006;81(4):1401-6.
23. Xie A, Lo P, Yan TD, et al. Neurologic complications of extracorporeal membrane oxygenation: a
review. J Cardiothorac Vasc Anesth. 2017;31(5):1836-46.
24. Bembea MM, Rizkalla N, Freedy J, et al. Plasma biomarkers of brain injury as diagnostic tools
and outcome predictors after extracorporeal membrane oxygenation. Crit Care Med. 2015;43(10):
2202-11.
25. Lubnow M, Philipp A, Foltan M, et al. Technical complications during veno-venous extracorporeal
membrane oxygenation and their relevance predicting a system-exchange-retrospective analysis
of 265 cases. PLoS One. 2014;9(12):e112316.
26. Sidebotham D, McGeorge A, McGuinness S, et al. Extracorporeal membrane oxygenation
for treating severe cardiac and respiratory failure in adults: part 2-technical considerations.
J Cardiothorac Vasc Anesth. 2010;24(1):164-72.
27. Diehl A, Gantner D. Pump head thrombosis in extracorporeal membrane oxygenation (ECMO).
Intensive Care Med. 2018;44(3):376-7.
28. Lehle K, Philipp A, Gleich O, et al. Efficiency in extracorporeal membrane oxygenation-cellular
deposits on polymethylpentene membranes increase resistance to blood flow and reduce gas
exchange capacity. ASAIO J. 2008;54(6):612-7.
29. Vogel AM, Lew DF, Kao LS, et al. Defining risk for infectious complications on extracorporeal life
support. J Pediatr Surg. 2011;46(12):2260-4.
30. Bizzarro MJ, Conrad SA, Kaufman DA, et al.; Extracorporeal Life Support Organization Task
Force on Infections, Extracorporeal Membrane Oxygenation. Infections acquired during
extracorporeal membrane oxygenation in neonates, children, and adults. Pediatr Crit Care Med.
2011;12(3):277-81.
31. Burket JS, Bartlett RH, Vander Hyde K, et al. Nosocomial infections in adult patients undergoing
extracorporeal membrane oxygenation. Clin Infect Dis. 1999;28(4):828-33.
32. Pieri M, Agracheva N, Fumagalli L, et al. Infections occurring in adult patients receiving mechanical
circulatory support: the two-year experience of an Italian National Referral Tertiary Care Center.
Med Intensiva. 2013;37(7):468-75.
33. Aubron C, Cheng AC, Pilcher D, et al. Infections acquired by adults who receive extracorporeal
membrane oxygenation: risk factors and outcome. Infect Control Hosp Epidemiol. 2013;34(1):
24-30.
34. Hsu MS, Chiu KM, Huang YT, et al. Risk factors for nosocomial infection during extracorporeal
membrane oxygenation. J Hosp Infect. 2009;73(3):210-6.
35. Kao LS, Fleming GM, Escamilla RJ, et al. Antimicrobial prophylaxis and infection surveillance in
extracorporeal membrane oxygenation patients: a multi-institutional survey of practice patterns.
ASAIO J. 2011;57(3):231-8.
36. Glater-Welt LB, Schneider JB, Zinger MM, et al. Nosocomial bloodstream infections in patients
receiving extracorporeal life support: variability in prevention practices: a survey of the
Extracorporeal Life Support Organization Members. J Intensive Care Med. 2016;31(10):654-69.
37. Lidegran MK, Mosskin M, Ringertz HG, et al. Cranial CT for diagnosis of intracranial complications
in adult and pediatric patients during ECMO:Clinical benefits in diagnosisand treatment. Acad
Radiol. 2007;14:62-71
CHAPTER 38
Extracorporeal Membrane
Oxygenation Weaning
Sandeep Dewan, Madhur Arora, Munish Chauhan

VENOARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION WEANING


Extracorporeal membrane oxygenation (ECMO) is an established strategy for circulatory
support in patients with cardiogenic shock. It is a modality used as a bridge to recovery or as
a bridge therapy to either implantation of ventricular assist device, or a heart transplantation.
One of the greatest challenges faced by the ECMO physicians is to find the optimum time for
weaning of venoarterial (VA) ECMO, when we know that there is no standardized process for
VA ECMO weaning yet. Very limited data is available on strategies for weaning from VA ECMO.
We must ensure that the patient is hemodynamically stable and cardiocirculatory dysfunction
is improving in the patient before initiating weaning. We must understand that weaning from
VA ECMO does not ensure a 100% survival. 35–80% of patients who are weaned off the VA
ECMO support survive and hence discharged from the hospital. This chapter will discuss the
various strategies for weaning proposed in the literature and the factors, which influence a
successful weaning in VA ECMO.

CRITERIA FOR WEANING


■ Etiology of cardiac dysfunction should be either recoverable or bridging to a therapy.
■ Improving cardiocirculatory function, ideally ejection fraction (EF) > 25–30%.
■ A pulsatile arterial waveform should be present for 24 hours.
■ Hemodynamic stable, with a mean arterial blood pressure (MAP) > 60 mm Hg in the
absence of any inotropic support or on minimal inotropic support (inotropic score less
than 10).
■ SpO2 >95%.
■ ScvO2 >70%.
■ No metabolic derangements.
■ Pulmonary function should not be severely impaired.
■ Patient must tolerate the weaning trial well.
Chapter 38  Extracorporeal Membrane Oxygenation Weaning 325

PREDICTORS OF WEANING
Patient should be assessed daily for clinical improvement, hemodynamic stability, and should
be evaluated for improving parameters on echocardiography before initiating a weaning
process. Various cardiac markers, which are indicative of myocardial recovery in patients not
on VA ECMO, are usually not of significance in patients of refractory cardiogenic shock on VA
ECMO as these markers are usually raised in various noncardiac conditions like, multiorgan
failure, sepsis, and renal disorders. However, in a study in 2012, Luyt and colleagues observed
that prognostic cardiac markers like Troponin I, N-terminal pro-brain natriuretic peptide (NT-
ProBNP), proadrenomedullin, and copeptin levels are usually raised in patients with refractory
cardiogenic shock on VA ECMO, but their kinetics do not predict any cardiac recovery during
the first week of the ECMO support. High lactate levels and an acidic arterial blood pH are
considered independent risk factors for mortality after eCPR in patients of VA ECMO.
Echocardiography plays an important role during the entire course of VA ECMO support
from initiation till weaning followed by decannulation. It helps to monitor recovery of the
cardiac function hence predicts the possibility of weaning of ECMO support. Echocardiographic
evaluation daily gives the physician information about systolic and diastolic function of the
heart, contractility of the heart, valvular abnormalities, and pericardial effusion. Hence, it
explains the factors leading to weaning failure and assesses the cardiac response after some
therapeutic intervention. Aissaoui et al. in 2011 identified clinical, hemodynamic, and Doppler
echocardiography parameters associated with successful ECMO removal in 51 patients of
refractory cardiogenic shock on VA ECMO due to medical (n = 27), postcardiotomy (n = 11),
or posttransplantation (n = 5) cardiogenic shock. The authors concluded that all patients
successfully weaned off VA ECMO had a left ventricular ejection fraction (LVEF) ≥ 20–25%, an
aortic velocity-time integral (VTI) of ≥10 cm and a lateral mitral annulus peak systolic velocity
(TDSa) of ≥6 cm/s at minimal ECMO support.
Echocardiographic findings usually seen during difficult weaning are:
■ Regional wall motion abnormalities
■ Right ventricular failure
■ Left ventricular failure
■ Systolic dysfunction
■ Diastolic dysfunction
■ Mitral regurgitation (postischemic)
■ Pericardial tamponade
■ Hypovolemia
■ Dynamic outflow tract obstruction
■ Pulmonary hypertension
Fiser et al. identified factors to predict weaning in VA ECMO in a group of postcardio-
tomy patients. They observed that elderly patients (>65 years) or patients with poor EF
(<30%) after 48 hours of ECMO were less likely to wean. Time on ECMO was significantly longer
for survivors in the heart transplant group compared to survivors in non-heart transplant
group.
326 Section 2  Extracorporeal Membrane Oxygenation

PROCEDURE OF WEANING
There is no standardized process of weaning of VA ECMO. The weaning strategy should be
individualized based on the initial indication of ECMO. Before initiating weaning, one must
ensure myocardial recovery, hemodynamic stability, and resolution of the primary cause of
cardiogenic shock.
Once the patient is hemodynamically stable with minimal or no inotropic support for more
than 24 hours and sufficient echocardiographic evaluation reveals a sufficient myocardial
function recovery, weaning can be initiated.
Weaning is initiated by progressively decreasing the ECMO blood flows. This reduced
blood flow increases the preload and decreases the afterload, thus augmenting stroke volume
and the cardiac output. Echocardiography is performed at each ECMO pump blood flow level
and cardiac function is continuously monitored. The ECMO blood flow is gradually reduced to
0.5–1.0 L/min. This low blood flow is maintained for approximately 40–60 minutes. Ventilatory
support is augmented progressively for the increasing pulmonary flows. The patient is
then observed for any hemodynamic instability, echocardiographic findings of ventricular
insufficiency and signs of inadequate perfusion like increase in blood lactate levels or a
significant fall in ScvO2. If any of these is found, it is advisable to restore full assistance and wait
till full recovery and start weaning process again.
When patient remains hemodynamically stable, off inotropes and LVEF is >25–30%,
patient maintains a saturation >95% and there are normal right ventricular pressures, removal
of ECMO can be considered.
Since the patient would be on heparin infusion, it is stopped and blood flows are increased
to avoid any clot formation in the circuit. After ensuring normal coagulation parameters
and normal platelet count, ECMO circuit is clamped and decannulation is performed in
the operation theater. The Extracorporeal Life Support Organization (ELSO) recommends
that anticoagulant drugs should be continued during the trial, and that the blood lines and
access cannulas should be periodically unclamped to avoid stagnation. The activated partial
thromboplastin time should be between 1.5 and 2.5 times the normal value.
Some institutes administer levosimendan at a dose of 0.1 μg/kg/min to improve both
systolic and diastolic function. The use of an intra-aortic balloon pump may improve survival
in ECMO patients. Petroni et al. identified that the use of an intra-aortic balloon pump in
patients receiving VA ECMO restored pulsatility and reduced left ventricular afterload, and
was associated with small left ventricular dimensions and low pulmonary artery pressure.
However, no study has assessed the value of intra-aortic balloon pumps during VA ECMO
weaning (Flowchart 1).

POST-WEANING
After successfully weaning the patient from the ECMO support, vigilant monitoring of the
vital parameters of the patient is essential. Continuous monitoring of SvO2, cardiac output,
peripheral perfusion, metabolic acidosis, lactates and urine output is essential for 24 hours
post decannulation.
Chapter 38  Extracorporeal Membrane Oxygenation Weaning 327
Flowchart 1: Stepwise weaning protocol for VA-ECMO.

(VA-ECMO: venoarterial extracorporeal membrane oxygenation; LVEF: left ventricular ejection fraction)

After decannulation, during the first hours, a systemic inflammatory response may be
seen with tachycardia, fever, and hypotension. This response can be managed with adequate
volume expansion and vasopressor support.
Signs of decreased cardiac output should be identified immediately and appropriate steps
should be carried out. Inotropic support should be optimized. In case of extreme hemodynamic
instability, despite maximal inotropic support, reimplantation of extracorporeal support must
be considered.
If left ventricular function remains severely depressed even after successful ECMO weaning,
cardiac resynchronization therapy (CRT) can be thought of.

FAILURE TO WEAN
Sometimes weaning a patient on ECMO becomes impossible. When the impossibility to
wean the patient off ECMO becomes clear, immediate identification of patients amenable to
long-term support or transplantation becomes imperative. Mechanical assist devices can be
considered either as a bridge therapy to transplantation or as a destination therapy.

VENOVENOUS EXTRACORPOREAL MEMBRANE OXYGENATION:


WEANING AND DECANNULATION
Discontinuation of the extracorporeal support is an integral part of the patient management.
328 Section 2  Extracorporeal Membrane Oxygenation

Table 1: Parameters of lung recovery.


Change in respiratory mechanics • Improved lung compliance
• Increased functional residual capacity seen on chest X-ray
Better gas exchange • Increase in PaO2 or decrease in PaCO2 on rest settings of the
ventilator
• Increased values of ETCO2 on rest settings of the ventilator
• Rapid improvement in SpO2 with increase in FiO2 to 100% (Cilley test)
Additional signs • Improved lung aeration on chest X-ray
• Resolving B-lines on lung ultrasonography

As the native lung function improves in patients on extracorporeal support, therapy is then
directed toward weaning off the extracorporeal support and later decannulation. Modalities
that might help hasten recovery in most patients include diuresis, antibiotic therapy, and
bronchoscopy and tracheal toileting.

Assessment of Weaning
Weaning a patient off the ECMO support is usually done by decreasing the extracorporeal
support as the native lung function improves. For patients on venovenous (VV) ECMO support
as well as “lung rest” ventilation, improvement of the pulmonary function can be assessed
even when the patient is still on full ECMO support. Improving oxygenation with rising
end-tidal CO2 on capnometry suggests improvement in alveolar gas exchange. Increased
pulmonary compliance (>20 cc/cm H2O) would lead to better tidal volume generation on
unchanged pressure control ventilator settings. Improvement in the aeration of chest X-ray
often accompanies improving alveolar recruitment. Cilley test should be performed daily in
patients showing improvement in lung parameters. The test involves increasing the FiO2 to
100% without changing any other parameter in the ventilator. A positive test is marked by
significant improvement in the oxygen saturation within a couple of minutes.
Parameters of lung recovery are as given in Table 1.

Process of Weaning
As the lung function starts improving and the native lung starts to contribute significantly
to arterial oxygenation, the extracorporeal blood flow is progressively decreased. In purely
hypercapnic patients where the extracorporeal blood flow is already low from the beginning,
sweep gas flow is altered. There is no standardized way of weaning patients off VV ECMO that
has been described in literature. Many centers prefer to decrease the FdO2 (oxygen fraction on
the ECMO machine) before switching off sweep gas, to avoid oxygen-related toxicity on the
native lung function.
Once the patient is found to be ready for weaning by the ECMO physician, it is suggested to
perform a trial of temporary discontinuation of the extracorporeal support. The following steps
are performed during a trial of VV ECMO discontinuation:
■ If the patient is on controlled mechanical ventilation, the ventilatory settings are adjusted
to values that are considered acceptable off the ECMO support. Care should be taken to
Chapter 38  Extracorporeal Membrane Oxygenation Weaning 329
ensure that the settings are not high and the ventilator FiO2 should be less than 70%. Mode
of ventilation will need to be tapered to patients’ needs. Assist control/SIMV/PSV/Bilevel
and APRV modes have been used successfully during ECMO weaning.
■ Once the ventilatory settings are adjusted, the sweep gas to the oxygenator is turned off.
However, it should be remembered that oxygen can leak around the flow meter even when
it is turned off, so it is important to clamp the gas tubes.
■ Once the sweep gas flow is switched off, the oxygen in the circuit is usually consumed
within 20 minutes.
■ It can be confirmed by looking at the color of the arterial and venous limb of the ECMO
circuit, which shows a similar color (dark red).
■ The extracorporeal flow is however continued and no adjustment of the heparin dosage is
made.
■ There are no clear-cut recommendations for the duration of weaning off ECMO. It varies
largely from anywhere between 1 hour and 6 hours.
■ During a trial off period, patient is closely monitored for the following:
– Hemodynamic stability: Heart rate, blood pressure, and continuous monitoring of
mixed venous oxygen saturations are recommended to evaluate the adequacy of
oxygen delivery during ECMO discontinuation.
– Adequacy of gas exchanges by serial monitoring of the arterial blood gas analysis.
– If the patient is on assisted spontaneous mode of ventilation, respiratory pattern and
mechanics (PIP, Pplat) and signs of respiratory distress are carefully observed.
■ If the patient remains stable during the trial off and his ventilatory load is acceptable,
the extracorporeal support can be definitely discontinued and decannulation can be
performed (Flowchart 2).

Anticoagulation Management
Usually, anticoagulation is continued throughout the trial-off period. If the patient passes
the trial off, ECMO flow is continued while the sweep gas remains off, and anticoagulation is
turned off in coordination with the plan for decannulation. If the patient then fails their trial off
VV ECMO, anticoagulation is continued as before and the extracorporeal support is restarted
with rest lung settings.

Checklist before Decannulation


■ Cardiopulmonary stability.
■ Ventilatory support reestablished, if it was reduced since trial off.
■ Blood gas to ensure adequate gas exchange.
■ Sedation/paralysis as required.
■ Blood and blood products as required.
■ Heparin infusion to be discontinued at least 30–60 minutes before the procedure.

Decannulation
Cannulas, which are percutaneously placed, can be removed directly. Some centers propose
to turn off heparin for 30–60 minutes before decannulation. Before cannula removal, a purse
330 Section 2  Extracorporeal Membrane Oxygenation

Flowchart 2: Stepwise weaning protocol for VV-ECMO.

(VV-ECMO: venovenous extracorporeal membrane oxygenation; ABG: arterial blood gas; PEEP: positive end-
expiratory pressure)

string suture is inserted around the cannulation site. Immediately after decannulation, the
suture is tightened and local pressure is applied for at least 30 minutes. The site is regularly
checked for the signs of bleeding or hematoma formation.
When removing the venous cannulas (especially jugular catheters) in spontaneously
breathing patients, there is a potential risk of air aspiration through the catheter’s side holes.
To avoid this complication, a Valsalva maneuver on the ventilator is performed at the time of
cannula removal. After removal of the percutaneously placed cannula, pressure needs to be
held at the venous puncture sites for at least 30 minutes.
After decannulation, a venous Doppler of the lower limbs and of the cannulated vessels
should be performed to exclude thrombotic events. Presence of clots should necessitate
anticoagulation and the need for inferior vena cava (IVC) filter should be evaluated.

Post Decannulation
Continued recovery is anticipated and attention is turned to further healing, rehabilitation,
and prevention of further complications. Some patients may develop worsening dyspnea. It
is important to think about differential diagnosis for the worsening condition (fluid overload,
Chapter 38  Extracorporeal Membrane Oxygenation Weaning 331
thromboembolism), performing appropriate diagnostic studies and using ventilator to support
respiratory function.
Systemic inflammatory response syndrome (SIRS) is a frequent phenomenon after ECMO
decannulation. Thangappan K et al. defined post-ECMO decannulation “SIRS phenomenon”
as having 2 out of 3 of the following criteria regardless of the presence of infection—fever
(temperature > 101.5°F), leukocytosis [white blood cell (WBC) > 12,000, or 25% increase from
pre-decannulation baseline], and escalation of vasopressors compared to the patient’s pre-
decannulation baseline. Other diagnostic criteria of SIRS, such as increase in heart rate or
respiratory rate were not used since these might be dependent on the use of inotropes, degree
of sedation, and ventilator settings. They showed that SIRS phenomenon can be observed as
early as first day of decannulation. Once patients developed the SIRS phenomenon after ECMO
decannulation, it could continue for almost a week regardless of the presence of infection.
Patients with the SIRS phenomenon with a suspected infection should be treated
aggressively with broad-spectrum antibiotics until culture results are available. Due to lack of
clear clinical differentiation between infection and the SIRS phenomenon, empiric antibiotics
have been advocated in these patients. We regularly administer a bolus dose of vancomycin
to all patients who get decannulated after 48 hours of ECMO run. The SIRS phenomenon
after ECMO decannulation should be treated as infection until proven otherwise in order to
optimize hospital outcomes.

Failure of Weaning
Sometimes weaning and trial off may not be successful. It is then that we would have to go to
full ECMO support again. Signs of weaning failure are:
■ Hypoxia
■ Hypercapnia
■ Respiratory distress
■ Hemodynamic instability.
The reason for weaning failure should be established and we need to look for causes
such as patient fatigue, worsening underlying pathology, new-onset sepsis, fluid overload or
inadequate ventilator settings. The cause should be identified using appropriate diagnostic
modalities like a repeat chest X-ray, HRCT chest, or ultrasonography of chest. After the
identification of the cause of failure, we need to take steps to correct reversible factors like
adequate rest to the patient before weaning, upgradation of antibiotics, achieve a negative
balance before weaning, and optimize ventilator settings. In case during trial off, there is only
retention of carbon dioxide (PaCO2 > 60 with pH < 7.25) with no hypoxemia, then continue
patient on ECMO or consider arteriovenous carbon dioxide removal (AVCO2R). Weaning
should be tried again after correction of the underlying cause.

Hypoxemia after Decannulation


In some circumstances, despite a successful weaning and trial-off followed by decannulation,
patient may become hypoxemic. In such cases, we might have to consider optimizing ventilator
settings, or reintubation if the patient had been extubated. Appropriate diagnostic modalities
332 Section 2  Extracorporeal Membrane Oxygenation

and appropriate management should be done as for any ARDS patient has to be done. One
may have to reconsider ECMO support after explaining the poor prognosis to the family.
John J et al. concluded in a study that complication rates are increased during the second
course of ECMO support in neonates. Specifically, neurologic, infectious, renal, and metabolic
complication rates are increased. Lyubomyr et al. also studied the outcomes of second-
run extracorporeal life support in children. They found out that survival after second-run
mechanical circulatory support in children was worse compared with single-run patients.
Long-term prospects for survivors were so grim that they did not recommend this strategy.

SUGGESTED READING
1. Aissaoui N, Luyt CE, Leprince P, et al. Predictors of successful extracorporeal membrane
oxygenation (ECMO) weaning after assistance for refractory cardiogenic shock. Intensive Care
Med. 2011;37(11):1738-45.
2. Bohuta L, d’Udekem Y, Best D, et al. Outcomes of second-run extracorporeal life support in
children: a single-institution experience. Ann Thorac Surg. 2011;92(3):993-6.
3. Brogan TV, Lequier L, Lorusso R, et al. Extracorporeal Life Support: The ELSO Red Book, 5th
edition. USA: Extracorporeal Life Support Organization; 2017.
4. Extracorporeal Life Support Organization. (2014). ELSO Anticoagulation Guidelines. [online]
Available from: https://www.elso.org/Portals/0/Files/elsoanticoagulationguideline8-2014-table-
contents.pdf. [Last accessed November, 2019].
5. Fiser SM, Tribble CG, Kaza AK, et al. When to discontinue extracorporeal membrane oxygenation
for postcardiotomy support. Ann Thorac Surg. 2001;71(1):210-4.
6. Luyt CE, Landivier A, Leprince P, et al. Usefulness of cardiac biomarkers to predict cardiac recovery
in patients on extracorporeal membrane oxygenation support for refractory cardiogenic shock.
J Crit Care. 2012;27(5):524.e7-14.
7. Meehan JJ, Haney BM, Snyder CL, et al. Outcome after recannulation and a second course of
extracorporeal membrane oxygenation. J Pediatr Surg. 2002;37(6):845-50.
8. Petroni T, Harrois A, Amour J, et al. Intra-aortic balloon pump effects on macrocirculation and
microcirculation in cardiogenic shock patients supported by venoarterial extracorporeal membrane
oxygenation. Crit Care Med. 2014;42(9):2075-82.
9. Sangalli F, Patroniti N, Pesenti A. ECMO-Extracorporeal Life Support in Adults. Italy: Springer;
2014.
10. Schmidt GA. Extracorporeal Life support for Adults. New York: Springer;2016.
11. Short BL, Williams L. ECMO Specialist Training Manual, 3rd edition. USA: Extracorporeal Life
Support (ELSO); 2010.
12. Thangappan K, Cavarocchi NC, Baram M, et al. Systemic inflammatory response syndrome (SIRS)
after extracorporeal membrane oxygenation (ECMO): incidence, risks and survivals. Heart Lung.
2016;45(5):449-53.
CHAPTER 39
Extracorporeal Membrane Oxygenation
Carbon Dioxide Removal
Ritu Airan, Poonam Malhotra Kapoor

INTRODUCTION
The most common cause, in critical care unit, is patient suffering from respiratory failure. This
condition is characterized by gas exchange that is not sufficient to satisfy the metabolic demand
of the body. In respiratory failure, acute respiratory syndrome (ARDS) is the leading cause,
which has been observed in critical care unit, leading to poor lung function, which in turn leads
to hypercapnia, hypoxia, and low respiratory compliance. In such conditions, mechanical
ventilation provides adequate oxygenation and carbon dioxide removal. Secondary injuries
to the lungs may be caused in such situation due to the homogeneous lung over distension.
In such condition, ventilator-induced lung injury (VILI) leads to multiple organ failure,
because of which there is no release of inflammatory mediators but proper oxygenation to the
body has led to the concept of the protective ventilation.
As compared with mechanical strategy, ultraprotective ventilation strategy is likely to
lead to hypercapnia and its deleterious consequences not only lead to systemic and cerebral
vasodilation but also cardiovascular depression, arrhythmia, which leads to increase
pulmonary arterial pressure. In such cases, without exposing lungs to mechanical ventilation
leads to lung trauma, hence the concept of extracorporeal carbon dioxide removal (ECCO2R)
has come up for the patients undergoing respiratory failure.

DEFINITION
Extracorporeal carbon dioxide removal achieves removal of carbon dioxide from the
body through a low blood flow (0.4–1 L/min) in the extracorporeal circuit without much
affecting the blood oxygenation, a kind of partial respiratory support. The concept of ECCO2R
is compared with the extracorporeal membrane oxygenation (ECMO) in which the blood flows
of 3–7 L/min has to be provided for total respiratory support. ECMO and ECCO2R support are
almost same, maintaining the difference in the blood flow rates that has to be maintained
according to the patient’s need. ECCO2R can also be referred as low flow ECMO by some
authors.
334 Section 2  Extracorporeal Membrane Oxygenation

MECHANISM OF EXTRACORPOREAL CARBON DIOXIDE REMOVAL


Lung rest is provided by removal of total carbon dioxide production and hence less mechanical
ventilation. The concept of ECCO2R was mainly to have carbon dioxide clearance in patients
with severe ARDS, by allowing to maintain the inspiratory pressure and tidal volume. Carbon
dioxide removal is also essential for patients needing ECMO for a bridge to heart and lung
transplant and also COPD patients. In routine ECMO and ECCO2R, the gas physiology differs
from each other. The oxygen transported is bound to the hemoglobin, rather than being
dissolved in the blood so that the 60–70% of mixed venous oxygen saturation, which has to
be achieved, can be added in blood to perfuse the lung or extracorporeal lung. The blood flow
of 4–7 L is given so that oxygenated blood flowing throughout the body and carbon dioxide
exchange depends on the ventilation whether supported by the lung or membrane. In case of
ECCO2R, the sweep gas passes through the membrane containing little or no carbon dioxide on
the other side of the semipermeable membrane of the blood creating the diffusion gradients,
which allows carbon dioxide removal. Gradients across capillary and alveolar wall in native
lung are lower as compared to membrane separating the blood from the gas phase by using the
sweep gas flow. Practically, it has been observed that the efficiency of gas exchange membrane
plays a vital role with other factors such as hemoglobin, sweep gas oxygen supplied and blood
flow. As blood flow is one of the important factors, hence the CO2 removal also varies with
changes in the blood flow, which also exhibits biphasic removal kinetics.

CHARACTERISTICS OF EXTRACORPOREAL CARBON DIOXIDE REMOVAL


Extracorporeal carbon dioxide removal system varies in characteristic, due to its efficiency of
removal of carbon dioxide; hence, gas exchange is better in respiratory failure patients. The
system in mechanical support ranges from renal dialysis system (low blood flow and low
priming volume) to the partial extracorporeal support in case of ECCO2R up to the full flow
system in ECMO patients. The design of ECCO2R circuit is such that it is easy to handle.
In case of arteriovenous (AV) system, the patient blood pressure is across the membrane
whereas in venovenous (VV) system, the pump is placed within the circuit through the access
cannula. Access to the circulation is gained in two ways either by separate arterial and venous
cannula or by double lumen cannula in VV system. Selection of arterial cannula’s size is smaller
as compared to the venous cannula. There is possibility of limb ischemia and artery injury,
in AV approach as compared with VV approach. Other complications such as compartment
syndrome, bleeding during cannulation, cannula thrombosis are also reported. It has been
made in practice the use of ultrasound of the artery, which is observed prior to the cannulation
of the artery, so that adequate size of cannula inserted in the artery of the patient is without
any injury, so that adequate blood flow is must which is directly related to the size and proper
insertion of the cannula by the experienced and skilled person. The complication observed in
VV ECCO2R is usually cannula thrombosis and sometimes the pump malfunction.

Cannula
In case of VV ECCO2R, heparin-coated double lumen cannula, which is wire reinforced, is used
to avoid any thrombosis risk during cannulation. Usually large veins are used for cannulation,
Chapter 39  Extracorporeal Membrane Oxygenation Carbon Dioxide Removal 335

Fig. 1: The membrane lung.

i.e. jugular and the femoral. Veins are most commonly used. Though modern generation
cannula available is heparin-coated, it is still recommended that patient is systematically
heparinized to avoid any thrombosis.

Membrane Lung
Modern hemodialysis filters and membrane lung is very similar, that uses blood which is
carried through capillary tubules, which is carried in the oxygenator that has separate tubules
to carry sweep gas. Microporous poly-4-methyl pentene (PMP) is most commonly used, which
has superior gas exchange quality with addition to its biocompatability and low resistance and
less susceptible to plasma leak. According to the requirement of the patients, blood flow rates
and sweep gas is given to the patients (Fig. 1).

Pump
There are no requirements of the pump in case of AV ECCO2R as patient’s own blood pressure
contributes by arterial blood, which is accessed through the arterial cannula, and blood is
returned back through venous cannula. Hence, it is cheaper and simpler to be used. In case
of VV ECCO2R system, blood flow is achieved through mechanical pump which may be roller
or centrifugal in conjunction with membrane which is again a separate component or in an
integrated form. Mostly centrifugal pumps are only used as roller pump have a disadvantage
of causing hemolysis and are not good for long duration support (Fig. 2).

CLINICAL EVIDENCE FOR EFFICACY OF CO2 REMOVAL


Kolobow and Gattinoni in 1976, has exploited that severe respiratory failure patient can be
treated by the use of low-frequency positive pressure ventilation along with extracorporeal
carbon dioxide removal (LFPV-ECCO2R).
336 Section 2  Extracorporeal Membrane Oxygenation

Fig. 2: The different centrifugal pumps.

Flowchart 1: Types of ECCO2R.

(ECCO2: extracorporeal carbon dioxide; VV: venovenous)

Respiratory acidosis is improved using ECCO2R or AV ECCO2R, which helps to remove


minute ventilation. Similarly, patient with ARDS, VV ECCO2R can reduce PaCO2 effectively and
thereby facilitate in both tidal volume and airway pressures.

TYPES OF ECCO2R (FLOWCHART 1)


■ Arteriovenous CO2 removal (AVCO2R)
■ Pumpless extracorporeal lung assist (PECLA)
■ Venovenous CO2 removal (VVCO2R)
Chapter 39  Extracorporeal Membrane Oxygenation Carbon Dioxide Removal 337
■ Typical ECMO setup
■ ILA active
■ Decap/Decapsmart
■ Hemolung
■ Gas exchange catheter
■ Respiratory dialysis.

DIFFERENT EXAMPLES OF ECCO2R MACHINES (FIGS. 3A TO D)

Fig. 3A: Novalung interventional lung assist.

Fig. 3B: Arteriovenous carbon dioxide removal (AVCO2R) or pump-less extra corporeal lung assist.
338 Section 2  Extracorporeal Membrane Oxygenation

Fig. 3C: Decap/Decap Smart (Hemodec, Salerno, Italy).


(UF: ultrafiltration)

Fig. 3D: Hemolung (Alung Technologies, Pittsburgh, USA).

ECCO2R COMPLICATIONS DURING THE VARIOUS STAGES


Catheter Insertion
■ Catheter-site bleeding
■ Catheter-site infection
Chapter 39  Extracorporeal Membrane Oxygenation Carbon Dioxide Removal 339
■ Inadvertent arterial insertion (in VV ECCO2R)
■ Catheter dislodgement or kinking of tubing
■ Hematoma, aneurysm, or pseudoaneurysm formation
■ Compartment syndrome
■ Distal limb ischemia (in AV ECCO2R).

Therapy
■ Worsening hypoxemia during lower tidal volume ventilation
■ Bleeding (related to anticoagulation)
■ Hemolysis
■ Heparin-induced thrombocytopenia
■ Acquired coagulopathy (e.g. acquired von Willebrand syndrome)
■ Air embolism
■ Recirculation.

Device Failure
■ Pump failure
■ Oxygenator failure
■ Heat exchanger malfunction
■ Clot formation
■ Air within circuit.

CURRENT EVIDENCE
As ECCO2R is a new concept, it was developed with an interest in its expansion along with many
other devices. Many devices are available in the market. The success of the patient recovering
from the respiratory syndrome depends on the ECCO2R system, the clinical situation in
which it has been used, and the skill of the individual handling the whole system with the
team. VV ECCO2R is more beneficial than AV ECCO2R as it involves minimal complication. At
present ECCO2R use remains only for research purposes till more scientific literature shows its
immense benefit on ECMO mortality outcomes.

SUMMARY
■ Coupling mild extracorporeal support device with ultraprotective ventilation represents
the most promising possibility in the treatment of respiratory failure patients to obtain best
therapeutic goals.
■ Venovenous extracorporeal carbon dioxide removal is more beneficial as compared to AV
ECCO2R in respiratory failure patients.
■ Like other mechanical therapy, ECCO2R is an emerging technique that could be used in
patients with severe respiratory failure with time and skill.
■ Venovenous extracorporeal carbon dioxide removal will be helpful even for the bridge for
lung transplant patient in near future.
■ Extracorporeal carbon dioxide removal is one of the mechanical therapies used in patient
associated with severe respiratory failure with time and skill.
340 Section 2  Extracorporeal Membrane Oxygenation

SUGGESTED READING
1. Batchinsky AI, Jordan BS, Regn D, et al. Respiratory dialysis: reduction in dependence on mechanical
ventilation by veno-venous extracorporeal CO2 removal. Crit Care Med. 2011;39(6):1382-7.
2. Bein T, Müller T, Graf BM, et al. Factors of tidal volume variation during augmented spontaneous
ventilation in patients on extracorporeal carbon dioxide removal. A multivariate analysis. Minerva
Anestesiol. 2015;81(1):28-32.
3. Bein T, Weber F, Philipp A, et al. A new pumpless extracorporeal interventional lung assist in
critical hypoxemia/hypercapnia. Crit Care Med. 2006;34(5):1372-7.
4. Cove ME, MacLaren G, Federspiel WJ, et al. Bench to bedside review: extracorporeal carbon
dioxide removal, past present and future. Crit Care. 2012;16(5):232.
5. Fitzgerald M, Millar J, Blackwood B, et al. Extracorporeal carbon dioxide removal for patients with
acute respiratory failure secondary to the acute respiratory distress syndrome: a systematic review.
Crit Care. 2014;18(3):222.
6. Flörchinger B, Philipp A, Klose A, et al. Pumpless extracorporeal lung assist: a 10-year institutional
experience. Ann Thorac Surg. 2008;86(2):410-7.
7. Gattinoni L, Agostoni A, Pesenti A,et al. Treatment of acute respiratory failure with low-frequency
positive-pressure ventilation and extracorporeal removal of CO2. Lancet. 1980;2(8189):292-4.
8. Gattinoni L, Pesenti A, Kolobow T, et al. A new look at therapy of the adult respiratory distress
syndrome: motionless lungs. Int Anesthesiol Clin. 1983;21(2):97-117.
9. Karagiannidis C, Kampe KA, Sipmann FS, et al. Veno-venous extracorporeal CO2 removal for the
treatment of severe respiratory acidosis: pathophysiological and technical considerations. Crit
Care. 2014;18(3):R124.
10. Kolff WJ, Berk HT, ter Welle M, et al. The artificial kidney: a dialyser with a great area. 1944. J Am
Soc Nephrol. 1997;8(12):1959-65.
11. Kolobow T, Gattinoni L, Tomlinson T, et al. An alternative to breathing. J Thorac Cardiovasc Surg.
1978;75(2):261-6.
12. Livigni S, Maio M, Ferretti E, et al. Efficacy and safety of a low-flow veno-venous carbon dioxide
removal device: results of an experimental study in adult sheep. Crit Care. 2006;10(5):R151.
13. MacLaren G, Combes A, Bartlett RH. Contemporary extracorporeal membrane oxygenation for
adult respiratory failure: life support in the new era. Intensive Care Med. 2012;38(2):210-20.
14. Marcolin R, Mascheroni D, Pesenti A, et al. Ventilatory impact of partial extracorporeal CO2
removal (PECOR) in ARF patients. ASAIO Trans. 1986;32(1):508-10.
15. Morimont P, Batchinsky A, Lambermont B. Update on the role of extracorporeal CO2 removal as
an adjunct to mechanical ventilation in ARDS. Crit Care. 2015;19:117.
16. Morimont P, Guiot J, Desaive T, et al. Veno-venous extracorporeal CO2 removal improves pulmonary
hemodynamics in a porcine ARDS model. Acta Anaesthesiol Scand. 2015;59(4):448-56.
17. Müller T, Lubnow M, Philipp A, et al. Extracorporeal pumpless interventional lung assist in clinical
practice: determinants of efficacy. Eur Respir J. 2009;33(3):551-8.
18. Park M, Costa EL, Maciel AT, et al. Determinants of oxygen and carbon dioxide transfer during
extracorporeal membrane oxygenation in an experimental model of multiple organ dysfunction
syndrome. PLoS One. 2013;8(1):e54954.
19. Pesenti A, Patroniti N, Fumagalli R. Carbon dioxide dialysis will save the lung. Crit Care Med.
2010;38(Suppl 10):S549-54.
20. Pesenti A, Pelizzola A, Mascheroni D, et al. Low frequency positive pressure ventilation with
extracorporeal CO2 removal (LEPPV-ECCO2R) in acute respiratory failure (ARF): technique. Trans
Am Soc Artif Intern Organs. 1981;27:263-6.
21. Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med. 2013;369(22):2126-36.
22. Terragni P, Maiolo G, Ranieri VM. Role and potentials of low-flow CO2 removal system in
mechanical ventilation. Curr Opin Crit Care. 2012;18(1):93-8.
Chapter 39  Extracorporeal Membrane Oxygenation Carbon Dioxide Removal 341
23. Terragni P, Ranieri VM, Brazzi L. Novel approaches to minimize ventilator-induced lung injury.
Curr Opin Crit Care. 2015;21(1):20-5.
24. Ventetuolo CE, Muratore CS. Extracorporeal life support in critically ill adults. Am J Respir Crit
Care Med. 2014;190(5):497-508.
25. Wearden PD, Federspiel WJ, Morley SW, et al. Respiratory dialysis with an active-mixing
extracorporeal carbon dioxide removal system in a chronic sheep study. Intensive Care Med.
2012;38(10):1705-11.
26. Zanella A, Mangili P, Giani M et al. Extracorporeal carbon dioxide removal through ventilation of
acidified dialysate: an experimental study. J Heart Lung Transplant. 2014;33(5):536-41.
27. Zanella A, Mangili P, Redaelli S, et al. Regional blood acidification enhances extracorporeal carbon
dioxide removal: a 48-hour animal study. Anesthesiology. 2014;120(2):416-24.
28. Zimmermann M, Bein T, Arlt M, et al. Pumpless extracorporeal interventional lung assist in patients
with acute respiratory distress syndrome: a prospective pilot study. Crit Care. 2009;13(1):R10.
CHAPTER 40
Extracorporeal Cardiopulmonary
Resuscitation
Kanwalpreet Sodhi, Gunjan Chanchalani, Anju Grewal

INTRODUCTION
Acute cardiac arrest has a poor prognosis even when advanced cardiac life support (ACLS)
is initiated without delay. Extracorporeal cardiopulmonary resuscitation (eCPR) is a novel
technique, which uses an extracorporeal life support system (ECLS) to reestablish vital organ
blood flow even with ongoing cardiac arrest. This technique was suggested by Kennedy in
1966, but the use of eCPR has recently become popular after the widespread use of ECLS
in H1N1 pandemic patients.1 In cardiac arrest patients undergoing eCPR, venoarterial
extracorporeal membrane oxygenation (VA ECMO) is performed during resuscitation, via
the femoral vein and artery access with large-bore cannulas which are connected to a pump-
driven extracorporeal circuit, that drains blood from the inferior vena cava, passes it over
a membrane oxygenator and delivers oxygenated blood back into the abdominal aorta;
thereby reestablishing vital organ perfusion.2 Even though return of spontaneous circulation
(ROSC) occurs in several patients after extracorporeal blood flow has been initiated, the
cause of cardiac arrest is not reversed by eCPR. Therefore, this technique must always be
combined with a diagnostic workup to identify the cause of cardiac arrest (5Hs and 5Ts),
and interventions to treat the underlying pathology. For an effective in- and out-of-hospital
eCPR program, system preparedness, capacity, training of personnel involved, and logistics
for eCPR should be in place.

DEFINITION OF EXTRACORPOREAL CARDIOPULMONARY RESUSCITATION


Extracorporeal cardiopulmonary resuscitation may be defined as the rapidly deployed
implantation of venoarterial extracorporeal membrane oxygenation (VA ECMO) in patients
who experience a sudden, unexpected cardiac arrest.3American Heart Association (AHA)
guidelines and Extracorporeal Life Support Organization (ELSO) guidelines now recognize
eCPR as a technique to be considered in specific cardiac arrest patients.4,5 Mobile ECMO
retrieval devices and services are an integral part of eCPR and involves a lot of organizational,
logistical, and clinical efforts.
Chapter 40  Extracorporeal Cardiopulmonary Resuscitation 343

INDICATIONS
The eCPR can be applied for supporting a patient for cerebral cardiopulmonary resuscitation
(cerebral CPR) as a:
■ “Bridge-to-Recovery” by providing time for diagnostic procedures, therapies to be delivered
or to insert the ventricular assist device
■ “Bridge-to-Organ transplantation” as a means to consider organ transplantation during
the arrest period
■ “Bridge-to-Decision” to continue or stop advanced cardiopulmonary support or as to a
bridge to palliative care plan.
The eCPR is a highly invasive, resource-intensive, and expensive technique, and therefore
needs careful selection of patient population. eCPR is usually carried out in patients who
continue to be in cardiac arrest despite conventional CPR, i.e. refractory cardiac arrest. eCPR
is indicated in patients with:
■ Witnessed cardiac arrest
■ Those undergoing continuous CPR
■ No response to conventional CPR
■ Reversible cause of cardiac arrest is present.
In the out-of-hospital cardiac arrest (OHCA) scenarios, other potential indications for
eCPR are:
■ Accidental hypothermia
■ Poisoning, particularly with sedative and/or cardiotoxic drugs.
Patients exhibiting ROSC during CPR or experiencing repeated cardiac arrest episodes
might be considered for eCPR even after prolonged periods of CPR.

CRITERIA TO BE FULFILLED BEFORE TAKING UP THE PATIENT FOR eCPR


For a successful eCPR outcome, following minimum criteria should be ideally fulfilled:
■ A well-established running eCPR program within the institute or within reach in a
reasonable time period
■ Preserved functional reserve of the patient before cardiac arrest
■ Reversibility of the underlying cause of cardiac arrest
■ Absence of severe hypoxic brain damage before establishing extracorporeal life support.

TIMING
Most of the guidelines recommend that eCPR should be implemented within 60 minutes
of collapse. For this, a program should be built according to local resources knowing that
the optimal team will require preestablished, specific roles with personnel dedicated to
conventional resuscitation and others to make preparation for eCPR. Extrapolation of data
from available literature suggests that eCPR should be considered:
■ Only in patients with witnessed collapse and in whom chest compressions have been
initiated within 10 minutes of the onset of cardiac arrest
■ Good functional recovery is more likely if the time from collapse to start of extracorporeal
blood flow is less than 60 minutes.
344 Section 2  Extracorporeal Membrane Oxygenation

CONTRAINDICATIONS
All contraindications to routine ECMO use apply to eCPR patients also. Poor candidates for
eCPR are:
■ Gestational age < 34 weeks
■ Weight 1.5 kg or less
■ Severe congenital abnormality
■ Concomitant major trauma
■ End-stage terminal illness or significant medical comorbidities, such as cachexia, obesity
or preexisting renal failure
■ Uncontrolled hemorrhage
■ Recent cerebral hemorrhage
■ Coagulopathy
■ Futile efforts: Unsuccessful CPR with no ROSC for 5–30 minutes
■ Do-not-resuscitate (DNR) orders.
Septicemia is not considered a contraindication for ECLS anymore. Guidelines for
neonatal and pediatric sepsis with refractory shock, now includes ECLS as a part of treatment
algorithm.6

INITIATION AND MAINTENANCE OF eCPR


Initiation
■ Decision-making related to initiation of ECLS should preferably be anticipatory, with a
predesignated individual (e.g. Code Blue Team Leader) who is authorized to request an
initiation of eCPR.
■ Immediate availability of ECLS equipment and rapidly deployable skilled personnel are a
prerequisite to prevent unnecessary delays in establishing extracorporeal support.
■ Decision for cannulation site is at the discretion of the cardiac surgical team. Ideally
cannula placement should be done in specialized areas such as the cardiac catheterization
or interventional radiology laboratory under direct guidance but is not mandatory.
■ Percutaneous cannulation of vessels for eCPR is only recommended if the access to the
vessels exists prior to CPR and should be performed only by skilled providers.
■ There is always a practical hindrance for arterial access with ongoing CPR.

Maintenance
■ During eCPR, cerebral cardiopulmonary resuscitation being the target, careful attention
is required to maintain an adequate cerebral perfusion. Once ECMO flow has been
established, target flow rate and perfusion pressure as per the diagnosis and age of the
patient should be discussed by the ECMO team. The circuit blood flow might need to be
increased to target perfusion pressures, and careful titration of gas flow should be done to
avoid hypo- or hypercapnia, so as to minimize secondary brain ischemia.
■ Neuroprotection during and after CPR is critical and therapies known to improve survival
and neurological outcomes after CPR such as hypothermia should be included in the eCPR
program also.
Chapter 40  Extracorporeal Cardiopulmonary Resuscitation 345
■ Post-resuscitation, neurological examination by a neurologist should be a standard
protocol after discontinuation of neuromuscular blocking agents and once hemodynamic
stability is achieved.

Mobile/Portable ECMO Devices7


First mobile ECMO support was initiated in 2005 in order to provide circulatory support to
candidates distant from specialized ECMO centers. Some of the currently available mobile
ECMO devices are:
■ The ELS system (Maquet, Rastatt, Germany)—first generation of a hand-held ECMO device,
weighing about 24 kg, consisting of a control and steering unit, and a multifunctional
holder system for the membrane oxygenator and centrifugal pump.
■ Cardiohelp (Maquet, Rastatt, Germany)—a second generation device, weighing
approximately 9 kg, is currently the smallest advanced ECMO device.
■ Further compact mini ECMO systems, weighing about 5 kg are under development,
consisting of an oxygenator with an integrated blood pump. Due to its small size and
weight, they are useful in pediatric population and can be easily carried.

Inter-hospital Transport on Extracorporeal Membrane Oxygenation8


The first described transport on ECMO was in 1977 by Barlett et al. Inter-hospital transport of
ECMO patients may be done via ground ambulance, helicopter, or via fixed wing aircraft. The
mortality reported during ECMO transport is up to 0.5%, despite the high complexity of the pro-
cedure. The key elements for successful transportation of patients on portable ECMO devices are:
■ Sufficient electric supply—for the ECMO pump, heater, and other equipment. The
embedded battery in mini ECMO systems provides support for about 90 minutes without
access of power supply. 7
■ Oxygen supply also should be adequate for the entire transport.
■ The involved staff should be dedicated and experienced in emergency medicine, ECMO
cannulation, ECMO physiology and technology.
■ Pre-transport checklists and timeouts, and continued training with simulations.

Termination/Weaning
The duration of eCPR vary in published reports. If there is ROSC, weaning of ECMO should be
planned as per institution’s ECMO guidelines. Usually, the dilemma is not whether to withhold
eCPR, but rather when to withdraw it, if the eCPR fails. Although it should be the clinicians’
prerogative to decide if eCPR is appropriate and when the intervention is considered futile,
but the ultimate choice is of the patient’s caregivers in consideration with the patient’s wishes
too. Therefore, offering support and guidance to the patient’s family is an essential component
of eCPR program.

HOW TO PERFORM AN EXTRACORPOREAL


CARDIOPULMONARY RESUSCITATION?
The eCPR is resource-intensive, labor-intensive, costly, and carries risk of complications. A
team-based protocolized approach, with clear role allocation and communication is a must
for a successful eCPR. The cannulation team of eCPR includes four members:
346 Section 2  Extracorporeal Membrane Oxygenation

1. Primary cannulator
2. Assistant cannulator
3. ECMO console operator
4. Sonographer to image the heart and blood vessels.
The team members may include cardiac surgeons, cardiac anesthetists, intensivists, and
perfusionists, as per experience.
It is important to remember that arterial pulsations and Doppler color differential are lost
in arrested patients with ongoing CPR.
Chest compressions may be paused to facilitate the needle puncture and insertion
of guidewire. However, this pause should be as short as possible and should not exceed
60 seconds, as uninterrupted chest compressions are of prime importance for a successful
outcome. Remaining calm with the aim to place the guidewire on first pass, will help in avoiding
vascular complications later. Once needle insertion and guidewire insertion has commenced,
no further defibrillation is done. Effective CPR and pulse checks continue to recognize ROSC.
Drug therapy (use of adrenaline, amiodarone, etc.) continues as per ACLS protocol. However,
administration of adrenaline boluses should be stopped once ECMO support is initiated to
reduce the possibility of inadvertent hypertension.
Smaller cannulas are preferred (venous access 19–21 Fr; arterial return 15–17 Fr). Insertion
of the distal perfusion cannula (“backflow” cannula) may be delayed until the patient is on
support and may be delayed up to 4 hours in view of other resuscitative/corrective measures.
However, it should be done as soon as the patient is stable, to avoid limb ischemia.
Before connecting the cannula to the corresponding limbs of the ECMO circuit, the
cannulator should ensure the circuit is free of air bubbles and there is no air-fluid level in
the oxygenator. An ECMO circuit blood flow of 3 L/min and fresh gas (oxygen) flow of 3 L/
min is usually sufficient. The pump speed is increased to 1,000 RPM prior to clamp removal
to prevent backward flow in the circuit. The patient is connected to a ventilator with reduced
minute ventilation, as pulmonary circulation is reduced when VA ECMO is initiated.
Attempts to identify and correct the etiology of the cardiac arrest are of paramount impor-
tance, once patient is started on ECMO. Other supportive management with targeted tempera-
ture management, insertion of central venous cannula, sedation should also be initiated.

COMPLICATIONS
In addition to the usual complications associated with ECMO, risk of intracranial hemorrhage
in eCPR is higher than in conventional CPR—most likely due to anticoagulation practices,
cannulation strategies, microemboli, inflammation, etc.

ADVANTAGES AND DISADVANTAGES


The advantages of applying VA ECMO during cardiopulmonary arrest include:
■ Stable and augmented organ perfusion
■ Allow providers to cease external chest compressions, thereby decreasing the trauma
stress, frequent interruptions, and resultant low flow state of manual external chest
compressions.
Chapter 40  Extracorporeal Cardiopulmonary Resuscitation 347
The main disadvantages of eCPR are:
■ Increased cost and resources
■ Labor intensive.

PREDICTORS OF SURVIVAL
Literature comparing outcomes in out-of-hospital cardiac arrest (OHCA) vs in-hospital cardiac
arrest (IHCA) suggest that survival is better in patients who experience IHCA. Since survival
decreases by 5% with each elapsed minute of CPR, with typically longer ECLS initiation time
in OHCA patients, thus the extended periods of inadequate cerebral and myocardial oxygen
delivery leads to decreased survival.
A detailed analysis by Jaski et al. showed that eCPR performed in the catheterization
laboratory was associated with significantly better survival than in other hospital locations
(50% vs. 15% long-term survival, P ≤ 0.001).9 This might be related to immediate availability of
ECLS equipment and skilled personnel in the catheterization laboratory.
The placing of patient on ECMO is only a bridge to support the circulation as an attempt
to have neurologically favorable survival, while definitive treatment for the underlying cause
of cardiac arrest is being pursued. Current data suggest that eCPR is associated with good
functional outcome in up to 30–40% of patients with cardiac arrest, especially when used in
the in-hospital setting.2 A meta-analysis of nine studies including 3,098 cardiac arrest victims
reported that the use of ECLS during cardiopulmonary resuscitation increased 30-day survival
by 13% (absolute increase; CI 95% 6–20%, P < 0.001, number needed to treat 7.7) and favorable
neurological outcome by 14% (absolute increase, CI 95% 7–20%, P < 0.0001, number needed to
treat 7.1) compared to standard ACLS.10
Bartos et al. have reported a 48% 3-month survival with intact neurological function with the
use of eCPR in OHCA ventricular fibrillation (VF) patients.11 A recent meta-analysis reported
that patients with cardiac arrests with initial shockable rhythms have more favorable outcome
in OHCA scenarios with the use of eCPR.12Another observational study in Japan has reported
better neurological outcomes in OHCA patients with refractory VF/pulseless VT, whereas if the
rhythm was converted to PEA/asystole prior to placement of patients on ECMO, the benefit
was decreased. The absolute time from the time of sudden cardiac arrest to initiation of eCPR
has no significant effect on outcomes.13 Also, the eCPR had a higher rate of completed targeted
temperature management (TTM), compared to conventional CPR (89% vs 46%). Favorable
neurological outcomes at 6 months in eCPR patients may be through TTM in patients with
sustained VF/pVT.13
Another recent study showed that >13% lactate clearance at 6 hours predicted a good
neurological outcome assessed by Glasgow Outcome Score. It concluded that lactate clearance
does not correlate with mortality, but can be used as a guide by clinicians to stop eCPR.14
Even in nonshockable initial rhythms, mostly PEA, Patricio D et al. found 13% patients
having a favorable neurological outcome15 Pabst D et al. also showed a 15–20% survival to
discharge in patients receiving eCPR, with initial PEA as a cause of sudden cardiac arrest.16
For patients with asystole as the initial cardiac arrest rhythm, eCPR has been reported to be
futile.16
348 Section 2  Extracorporeal Membrane Oxygenation

ETHICAL CONSIDERATIONS
Extracorporeal cardiopulmonary resuscitation was initially a rescue therapy for cardiac arrests
in the hospital.1 However, studies and reviews since the late 1980s, have increasingly suggested
eCPR as a feasible option for OHCA adult patients as well.17
The main ethical issue is to choose between continuing conventional CPR with
uninterrupted, effective compressions; or to move patients and expose them with the avoidable
risk involving transportation and placing on ECMO and increasing circulatory downtime.18 On
the other hand, in truly refractory VF/VT, the chances of survival may reduce substantially with
only conventional CPR. Randomized trials suggesting criteria for appropriate patient selection
for early and judicious use of eCPR are needed.19
Due to the time sensitivity involved with initiation of eCPR, the decision-making for the
same is seldom shared with next of kin, and is usually medically driven. The next of kin is
often involved later in the process after ECMO has been initiated and at times, late enough to
consent regarding withdrawal of life supporting system when ECMO is more of a “bridge-to-
nowhere”.20 The ethical principle of patient autonomy is often challenged in such situations
of “bridge-to-nowhere”. Further experience is needed whether involving the next of kin in the
emergency for the decision-making process is feasible, especially when the situation both
complex and uncertain.
The evidence regarding use of eCPR in sudden cardiac arrest scenarios is limited and
not uniform. Though few RCTs have been done, majority of the data is derived from cohort
studies,17 but often the data is incomplete, biased, and often the outcome measure is not
patient reported.21 In this era of evidence-based medicine, using a costly as well as resource-
intensive therapy is major ethical concern.

COST-EFFECTIVENESS
The eCPR is highly resource demanding, and has a huge cost burden. To determine a threshold
value to assess the cost effectiveness of a therapy is highly challenging. Also, the survival rate and
quality of life following eCPR, contribute to the analysis.
A recent retrospective analysis of eCPR for 6 years from 2012 to 2018 at Chicago Medical
center, found the therapy cost-effective at their institution.22 Similarly, another recent study
conducted by the Sydney ECMO research interest group, found eCPR, a cost-effective
technique for refractory cardiac arrests.23 It also reported that the higher costs involved with
eCPR in IHCA patients, compared to OHCA patients, were offset by the higher survival rate
and increased mean quality-adjusted life year (QALY) in these set of patients. They also found
a similar cost-effective ratio between eCPR and conventional CPR. It is estimated that cost-
effectiveness will be better with eCPR, when the higher neurological favorable survival is
proven with the use of eCPR.

COMPARISON WITH CONVENTIONAL CARDIOPULMONARY RESUSCITATION


In order to improve CPR quality and survival in OHCA, the approach used by EMS providers
favored “stay and play” in order to decrease circulatory downtime.24 Whereas, eCPR demands
Chapter 40  Extracorporeal Cardiopulmonary Resuscitation 349
an approach of “load and go” for OHCA patients. It involves early recognition of refractory
cardiac arrest and a predominant cause of cardiac arrest being coronary artery disease.20
If eCPR is initiated too early, there is a possibility of exposing the patients to risks of ECMO,
who may have possibly recovered with conventional cardiopulmonary resuscitation (CCPR).
On the other hand, delaying the initiation, increases the possibility of anoxic brain damage.
The cutoff time for initiation of eCPR, to have good neurological outcomes is yet to be defined.
In a recently published retrospective study of 635 patients over a 5-year period, authors
reported a better long-term neurologically favorable outcome in patients who received eCPR
compared to CCPR. In patients who received CCPR, favorable neurological outcome was seen
in patients with time to ROSC < 45 minutes, whereas in patients who received eCPR, favorable
outcome was seen even with longer times to ROSC. On subgroup analysis, higher survival and
long-term neurologically favorable outcome was seen in patients with noncardiac cause of
arrest, who received eCPR compared to CCPR.15 In another study, survival rate with eCPR in
IHCA patients was reported to be twice of CCPR.25 Similarly, in another study on patients with
OHCA, patients subjected to eCPR group had a survival rate of 29% compared to 8% in the
CCPR group.26

EXTRACORPOREAL CARDIOPULMONARY RESUSCITATION IN


PEDIATRIC POPULATION
In 2016, ELSO reported 11% of total pediatric ECMO use in cardiac arrest scenario. The highest
use is in the neonates (36% of total neonatal ECMO).27 ELSO also reports initiation of eCPR
in less than 60 minutes of conventional CPR.28 The highest use is in the congenital cardiac
surgery cases, where no obvious cause of cardiac arrest is found in postcardiac surgery cases.
In such a scenario, ECMO cannulation should be done within 5 minutes of resternotomy, if no
tamponade or any other cause of cardiac arrest is identified.29
Unlike adults, femoral vessels are not an option for cannulation. Neck vessel cannulation
or central cannulation is used. The advantage of using neck vessels is that it does not require
interruption of chest compressions, whereas central cannulation requires surgical placement,
with interruption of compressions.30
However, neck cannulation carries the risk of thromboembolism and subsequent cerebral
infarction. To avoid this complication, some centers ligate the distal internal carotid artery,
and others reconstruct the artery after cannula explantation. With use of central vessels for
cannulation, this risk is not there as both internal carotid arteries are well perfused. Another
advantage of central cannulation is higher flow rates as bigger size of target vessels enable use
of larger-diameter cannulae.30
The survival to discharge with use of eCPR in the pediatric population is between 29% and
43%.27,28 This range varies as per the age group, and whether the arrest was in-hospital or out-
of-hospital. Prematurity is an important risk factor for poor survival, with the overall rate of
survival to discharge being 21%, 31%, and 41% in neonates with gestational age < 34 weeks,
< 37 weeks and full term, respectively.27
Data regarding long-term neurodevelopmental outcome in survivors after pediatric eCPR
is still lacking and greater research and follow-up is needed.
350 Section 2  Extracorporeal Membrane Oxygenation

CURRENT GUIDELINES ON USE OF EXTRACORPOREAL


CARDIOPULMONARY RESUSCITATION
The American Heart Association (AHA) guidelines suggest that there is insufficient evidence
to recommend the routine use of eCPR for patients with cardiac arrest. In settings where it can
be rapidly implemented, eCPR may be considered for select cardiac arrest patients for whom
the suspected etiology of the cardiac arrest is potentially reversible during a limited period of
mechanical cardiorespiratory support (Class IIb recommendation).4
European Resuscitation Council (ERC) guidelines suggest that eCPR should be considered
as a rescue therapy for those patients in whom ACLS measures are unsuccessful and/or to
facilitate specific interventions such as coronary angiography and percutaneous coronary
intervention or pulmonary thrombectomy for massive pulmonary embolism.31

THE FUTURE
Extracorporeal cardiopulmonary resuscitation is a reassuring form of resuscitation in
treatment of many fatal arrest conditions, especially of cardiac etiology and trauma. However,
optimal outcomes can be possible in systems with high level of commitment.

SUMMARY
■ Extracorporeal cardiopulmonary resuscitation is a potentially interesting technique to
improve survival with good neurological outcome in some selected patients with acute
cardiac arrest.
■ Use of eCPR is increasing in the pediatric population and is now considered an integral
part of congenital cardiac surgical programs.
■ eCPR may help solid organ retrieval from patients who could not be saved.
■ A well-established eCPR protocol has to be in place for successful outcomes.
■ Further research and experience is needed to address the ethical principles and develop
protocols for appropriate patient selection and the consent and decision process.

REFERENCES
1. Cardiopulmonary resuscitation. JAMA. 1966;198(4):372-9.
2. Fagnoul D, Combes A, De Backer D. Extracorporeal cardiopulmonary resuscitation. CurrOpin Crit
Care. 2014;20(3):259-65.
3. Soar J, Nolan JP, Böttiger BW, et al.;Adult advanced life support section Collaborators. European
Resuscitation Council Guidelines for Resuscitation 2015. Section 3. Adult advanced life support.
Resuscitation. 2015;95:100-47.
4. Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult Advanced Cardiovascular Life Support:
2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and
Emergency Cardiovascular Care. Circulation. 2015;132(18 Suppl 2):S444-64.
5. ELSO ECPR Supplement to the ELSO General Guidelines Extracorporeal Life Support Organization
(ELSO) Guidelines for ECPR Cases. 2013. [online] Available from: https://www.elso.org/Portals/0/
IGD/Archive/FileManager/6713186745cusersshyerdocumentselsoguidelinesforecprcases1.3.pdf.
[Last accessed November, 2019].
Chapter 40  Extracorporeal Cardiopulmonary Resuscitation 351
6. Brierley J, Carcillo JA, Choong K, et al. Clinical practice parameters for hemodynamic support
of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care
Medicine. Crit Care Med. 2009;37(2):666-88.
7. Merkle J, Djorjevic I, Sabashnikov A, et al. Mobile ECMO - A divine technology or bridge to
nowhere? Expert Rev Med Devices. 2017;14(10):821-31.
8. Ericsson A, Frenckner B, Broman LM. Adverse events during inter-hospital transports on
extracorporeal membrane oxygenation. Prehosp Emerg Care.2017;21(4):448-55.
9. Jaski BE, Ortiz B, Alla KR, et al. A 20-year experience with urgent percutaneous cardiopulmonary
bypass for salvage of potential survivors of refractory cardiovascular collapse. J Thorac Cardiovasc
Surg. 2010;139(3):753-7.e1-2.
10. Ouweneel DM, Schotborgh JV, Limpens J, et al. Extracorporeal life support during cardiac arrest
and cardiogenic shock: a systematic review and meta-analysis. Intensive Care Med. 2016;42(12):
1922-34.
11. Bartos JA, Carlson K, Carlson C, et al. Surviving refractory out-of-hospital ventricular fibrillation
cardiac arrest: Critical care and extracorporeal membrane oxygenation management. Resuscitation.
2018;132:47-55.
12. Debaty G, Babaz V, Durand M, et al. Prognostic factors for extracorporeal cardiopulmonary
resuscitation recipients following out-of-hospital refractory cardiac arrest: a systematic review and
meta-analysis. Resuscitation.2017;112:1-10.
13. Nakashima T, Noguchi T, Tahara Y, et al.; SAVE-J Group. Patients with refractory out-of-cardiac
arrest and sustained ventricular fibrillation as candidates for extracorporeal cardiopulmonary
resuscitation- prospective multi-center observational stud. Circ J. 2019;83(5):1011-8.
14. Jung C, Bueter S, Wernly B, et al. Lactate clearance predicts good neurological outcomes in cardiac
arrest patients treated with extracorporeal cardiopulmonary resuscitation. J Clin Med 2019;8(3).
pii: E374.
15. Patricio D, Peluso L, Brasseur A, et al. Comparison of extracorporeal and conventional
cardiopulmonary resuscitation: a retrospective propensity score matched study. Crit Care.
2019;23(1):27.
16. Pabst D, Brehm CE. Is pulseless electrical activity a reason to refuse cardiopulmonary resuscitation
with ECMO support? Am J Emerg Med. 2018;36(4):637-40.
17. Ortega-Deballon I, Hornby L, Shemie SD, et al. Extracorporeal resuscitation for refractory out-
of-hospital cardiac arrest in adults: a systematic review of international practices and outcomes.
Resuscitation. 2016;101:12-20.
18. Holmen J, Hollenberg J, Claesson A, et al. Survival in ventricular fibrillation with emphasis on
the number of defibrillations in relation to other factors at resuscitation. Resuscitation. 2017;113:
33-8.
19. Yannopoulos D, Bartos JA, Martin C, et al. Minnesota resuscitation consortium’s advanced
perfusion and reperfusion cardiac life support strategy for out-of-hospital refractory ventricular
fibrillation. J Am Heart Assoc. 2016;5(6). pii: e003732.
20. Henry B, Verbeek PR, Cheskes S. Extracorporeal cardiopulmonary resuscitation in out-of-hospital
cardiac arrest: ethical considerations. Resuscitation.2019;137:1-6.
21. Haywood K, Dainty KN. Life after cardiac arrest: the importance of engaging with the ‘forgotten
patient’. Resuscitation. 2018;128:A1-2.
22. Bharmal M, Venturini JM, Chua RF, et al. Cost-utility of extracorporeal cardiopulmonary
resuscitation in patients with cardiac arrest. Resuscitation. 2019;136:126-30.
23. Dennis M, Zmudzki F, Burns B, et al. Cost effectiveness and quality of life analysis of extracorporeal
cardiopulmonary resuscitation (ECPR) for refractory cardiac arrest. Resuscitation. 2019;139:49-56.
24. Smith RM, Conn AK. Prehospital care - scoop and run or stay and play? Injury. 2009;40(Suppl
4):S23-6.
352 Section 2  Extracorporeal Membrane Oxygenation

25. Maekawa K, Tanno K, Hase M, et al. Extracorporeal cardiopulmonary resuscitation for patients
with out-of-hospital cardiac arrest of cardiac origin: a propensity-matched study and predictor
analysis. Crit Care Med. 2013;41(5):1186-96.
26. Blumenstein J, Leick J, Liebetrau C, et al. Extracorporeal life support in cardiovascular patients
with observed refractory in-hospital cardiac arrest is associated with favorable short and long-term
outcomes: a propensity-matched analysis. Eur Heart J Acute Cardiovasc Care. 2016;5(7):13-22.
27. Thiagarajan RR, Barbaro RP, Rycus PT, et al.; ELSO member centers. Extracorporeal Life Support
Organization Registry International Report 2016. ASAIO J. 2017;63(1):60-7.
28. Barbaro RP, Paden ML, Guner YS, et al.; ELSO member centers. Pediatric Extracorporeal Life
Support Organization Registry International Report 2016. ASAIO J. 2017;63(4):456-63.
29. Erek E, Aydin S, Suzan D, et al. Extracorporeal cardiopulmonary resuscitation for refractory cardiac
arrest in children after cardiac surgery. Anatol J Cardiol. 2017;17(4):328-33.
30. Erdil T, Lemme F, Konetzka A,et al. Extracorporeal membrane oxygenation support in pediatrics.
Ann Cardiothorac Surg. 2019;8(1):109-15.
31. Monsieurs KG, Nolan JP, Bossaert LL, et al.; ERC Guidelines 2015 Writing Group. European
Resuscitation Council Guidelines for Resuscitation 2015: Section 1. Executive summary.
Resuscitation. 2015;95:1-80.
CHAPTER 41
Cardiac Issues in Extracorporeal
Membrane Oxygenation
Bhanu P Zawar, Yatin Mehta

INTRODUCTION
Extracorporeal membrane oxygenation (ECMO) is a type of extracorporeal life support system,
where an artificial circuit carries deoxygenated venous blood to an oxygenator to saturate it
with oxygen and remove carbon dioxide from it. This oxygenated blood then reenters the
native circulation again using a pump, either roller or centrifugal. Circulatory support can also
be provided by ECMO. The technology used in ECMO was evolved from cardiopulmonary
bypass (CPB) which also allows gas exchange outside the human body.
Management of cardiac failure has evolved exponentially over many decades. Management
ranges from various oral and intravenous drugs to intra-aortic balloon pump (IABP), various
mechanical circulatory devices such as left ventricular assist devices, biventricular assist
devices, right ventricular assist devices, and percutaneous ventricular assist devices. During
the H1N1/2009 pandemic, ECMO gained popularity when physicians encountered with severe
refractory, and rapidly progressive hypoxemia in young individuals. There are many reviews
on the ECMO for cardiac failure, cardiogenic shock, and cardiac arrest in the literature.1-5 We
will discuss mainly the cardiac complications of ECMO. First ECMO was successfully used by
cardiac surgeon Dr Robert Bartlett in US for neonatal respiratory distress syndrome in 1972.
Survival with venoarterial extracorporeal membrane oxygenation (VA) ECMO remains lower
(30–40%) compared from venovenous extracorporeal membrane oxygenation (VV) ECMO
(50–60%) in Extracorporeal Life Support Organization (ELSO) registry.

TYPES OF EXTRACORPOREAL MEMBRANE OXYGENATION


There are mainly three types of ECMO. Table 1 focuses on few types of ECMO. Figure 1 explains
VA ECMO.
1. Venoarterial ECMO: It provides gas exchange as well as hemodynamic support and blood is
pumped to arterial side from venous side. It acts as a parallel circuit to patients’ circulatory
system.
354 Section 2  Extracorporeal Membrane Oxygenation

Table 1: Extracorporeal membrane oxygenation types.


Property VA ECMO VV ECMO
Cannulation site IJV/FV and RCC/Ax/FA/Ao IJV alone/IJV-FV/ FV-FV/Saphsaph/RA
PaO2 60–150 mm Hg 45–80 mm Hg
Indicator of O2 Mixed venous oxygen saturation or PaO2 Combination of SaO2, PaO2, cerebral
sufficiency venous saturation and premembranous
saturation trend
Cardiac effect ↓ preload; ↑ afterload; pulse pr ↓; improve Negligible effects; may improve coronary
coronary oxygenation by LV blood; ‘Cardiac oxygenation; may reduce RV afterload
stun’
O2 delivery capacity High Moderate ↑ cephalad drain
Circulatory support Partial to complete Indirect: ↑ delivery of O2 to coronary and
pulmonary circulation
Ao: axillary; Ax: aortic; ECMO: extracorporeal membrane oxygenation; FA: femoral; IJV: internal jugular vein; FV:
femoral vein; LV: left ventricular; RA: right atrium; RCC: right common carotid; VA ECMO: venoarterial ECMO;
VV ECMO: venovenous ECMO. Saph-Saph: sapheno-saphenous

Fig. 1: Diagrammatic representation of various mechanical components and cannulation site of VA ECMO.
(VA ECMO: venoarterial extracorporeal membrane oxygenation)
Chapter 41  Cardiac Issues in Extracorporeal Membrane Oxygenation 355

Table 2: Various contraindications of extracorporeal membrane oxygenation.


Absolute contraindications Relative contraindications
Irreversible neurological conditions Severe peripheral vascular disease (VA ECMO)

Terminal malignancy Multiorgan failure


Aortic dissection (VA ECMO) Severe bleeding
Severe AR (VA ECMO) Age > 65 years
(ECMO: extracorporeal membrane oxygenation; VA ECMO: venoarterial ECMO)

Table 3: Various complications of extracorporeal membrane oxygenation.


Circuit-related or mechanical complication Patient-related complication
• Circuit tubing rupture • Bleeding
• Pump failure • pH imbalance
• Cannula-related problems • Limb ischemia
• Oxygenator (leakage) • Air embolism/thromboembolism
• Heat exchanger (thrombosis) • Sepsis, and cardiac, renal and GI complications
• Tubing embolism
(GI: gastrointestinal)

2. Venovenous ECMO: It provides gas exchange only. Blood is taken from a large vein and after
oxygenation returned back to it before it goes to pulmonary circulation. It is generally used
for pure respiratory failure.
3. Arteriovenous ECMO: It also provides gas exchange only, but utilizes patient’s blood
pressure as a force to move blood from arterial to venous side.

INDICATIONS
Criteria for the use of ECMO may include severe acute pulmonary or cardiac failure or both
that is likely to be reversible in near term and unresponsive to conventional treatment.

CONTRAINDICATIONS
Extracorporeal membrane oxygenation cannot be used in few patient populations.6-8
Table 2 lists few conditions in which ECMO is contraindicated (absolute or relative).
Table 1 differentiates between VA ECMO and VV ECMO. Figure 1 illustrates various mechani-
cal components and cannulation sites of a VA ECMO.

COMPLICATIONS
Managing a patient on ECMO is challenging. It is because use of ECMO is not without risks.
The complications associated with ECMO can be divided into two major categories (Table 3):
1. Mechanical or circuit-related complications
2. Patient-related complications (Table 3)
356 Section 2  Extracorporeal Membrane Oxygenation

Some specific complications are related to VA ECMO. These are:


■ Left ventricular (LV) distension
■ Cardiac thrombosis
■ Differential hypoxemia
■ Other common complication includes hypotension, hypertension, hemolysis, cardiac
arrest, etc.
Most of the cardiac complications occur with VA ECMO. We will discuss these complications
one by one. For other noncardiac complications of ECMO one may refer to these manuscripts.9-11

Left Ventricular Distension


One of the common complications occurs primarily due to the increased afterload caused by
extracorporeal blood flow. VA ECMO drains venous blood from heart, so, there is reduction
in the LV) preload. Also, VA ECMO improves aortic (and coronary) blood flow. But cardiac
function can also be depressed by VA ECMO as it returns blood retrogradely into the aorta. This
leads to increase in the afterload of the LV. Blood from the bronchial, thebesian and pulmonary
veins does not participate in VA ECMO circuit. The native blood flow within the heart is
reduced and aortic valve does not open up. LV blood stagnation and distension of LV occurs.
Retrograde blood flow by VA ECMO enhances any prior aortic incompetence which leads to
reduced forward flow across the aortic valve which further contributes to LV distension.
This distended LV can lead to:
■ Left ventricular ischemia
■ Left ventricular rupture
■ Left ventricular thrombus formation
■ Pulmonary hemorrhage
■ Pulmonary edema.
The diagnosis of LV distension can be made by chest X-ray or echocardiography. We can see
distended, noncontractile LV with aortic valve barely or not moving at all. Echocardiographic
image of distended LV is shown in Figure 2.
Left ventricular distension can be cured by:
■ Placing a pigtail inside the LV cavity
■ Surgically placing a vent in the LV/LA
■ Intra-aortic balloon pump insertion
■ Using percutaneous left ventricular assist device (LVAD)
■ Pulmonary artery drainage
■ Atrial septostomy
■ Inotropic support.

Cardiac Thrombosis
Intracardiac thrombus especially in LV cavity occurs due to motionless chamber, blood
activation after contact with foreign surfaces, and stasis of blood inside LV cavity. We should
allow at least some ejection of the blood from LV across the aortic valve so that cardiac
thrombosis can be prevented. Frequent echocardiographic examination is done for the
diagnosis of cardiac thrombosis. Little can be done once LV thrombus is formed in such a sick
patient. Weaning from VA ECMO becomes difficult once it is detected, but if VA ECMO was
used as a bridge to cardiac transplantation then LV thrombus is of less importance.
Chapter 41  Cardiac Issues in Extracorporeal Membrane Oxygenation 357

Fig. 2: Subcostal view of transthoracic echocardiography showing distended left ventricle.

DIFFERENTIAL HYPOXIA
Differential hypoxia occurs because LV perfuses upper body with deoxygenated and ECMO
perfuse lower body with oxygenated blood through femoral arteries. It can be detected by
differential oxygen saturation levels in lower and upper part of the body. This is known as
“Harlequin syndrome”.
Differential hypoxia can be treated by:
■ Increasing the pump flow
■ Increasing positive end-expiratory pressure (PEEP)/FiO2/ventilation
■ We can even recite the ECMO return line from femoral to subclavian artery.

Bleeding
Bleeding is the most common complication associated with VA ECMO support compared to
VV ECMO. Bleeding is due to heparin or direct thrombin inhibitors which are continuously
administered during ECMO, which prevents blood clotting and keeps the ECMO circuit
flowing smoothly. Also, there is platelet destruction and consumption coagulopathy which
aids to bleeding. Activated clotting time (ACT) is monitored, and heparin dose is carefully
controlled to prevent bleeding complications. Bleeding may be at surgical sites, or may occur
at intrapulmonary, intra-abdominal, or retroperitoneal sites. Uncommonly, life-threatening
intracranial bleeding can also occur. If bleeding occurs, we should stop heparin and have close
watch on ACT. We can transfuse platelets, fresh-frozen plasma (FFP), cryoprecipitate, and
packed cells, as needed.

Thromboembolism
Clotting can occur inside the circuit, despite anticoagulation therapy due to contact activation
of blood, blood stasis inside the capacitance vessel, or disseminated intravascular coagulation.
358 Section 2  Extracorporeal Membrane Oxygenation

Table 4: Weaning from VA ECMO.


• Circuit flow reduced to less than 2.5 L
• Increase anticoagulation
• Monitor hemodynamics and echo (heart function)
• Appropriate ventilator settings
• Once weanable: ECMO flows at least 2.5 L till ECMO decannulation
(ECMO: extracorporeal membrane oxygenation; VA ECMO: venoarterial ECMO)

Thrombus affects the functioning of the oxygenator and pump. It can lead to cerebrovascular
accidents, renal, limb, or splenic infarcts.

Sepsis
Infection can be a serious issue in ECMO patients and prevention by stringiest aseptic
precautions is the key. Prophylactic antibiotics are not routinely recommended.12

Air Embolism
Accidental decannulation and/or ECMO circuit rupture can lead to air embolism. The ECMO
circuit and pump will soon be filled with air and froth and pumping will not occur. Cardiac
arrest will occur in VA ECMO and profound hypoxia will occur in VV ECMO.
If air embolism occurs inside the venous circulation then we should immediately clamp
the circuit and start the cardiopulmonary resuscitation (CPR). Trendelenburg position should
be immediately restored. We can aspirate air with a Swan-Ganz catheter or central line. If air
embolism occurs into the arterial circulation then we should immediately clamp the circuit
and should start the CPR. Neuroprotective measures like hypothermia should be considered
as soon as possible.

Cardiac Arrest
Cardiac arrest in the VA ECMO is not considered as a major problem. It is because myocardium
plays a minor role in circulatory process. The ECG may show ventricular fibrillation, asystole,
etc. but the VA ECMO provides sufficient circulation to organ perfusion. A major hazard in an
immobile LV on VA ECMO is LV distension as we have seen above.
In a VV ECMO, the cardiac arrest can be dangerous, as there will be no cardiac output. The
venous access pressure will obviously fail or decrease. Immediately CPR should be started. The
“Airway” and “Breathing” parts of the advanced life support can be completely neglected if we
are able to maintain the ECMO flows as oxygenated blood will be provided by the VV ECMO
(Table 4).

EXTRACORPOREAL MEMBRANE OXYGENATION AS


A BRIDGE TO CARDIAC TRANSPLANTATION
Extracorporeal membrane oxygenation provides short-term mechanical circulatory support
only. It cannot provide long-term circulatory support due to membrane blockage and various
complications associated with it as we have seen above. Fukuhara studied patient on ECMO
Chapter 41  Cardiac Issues in Extracorporeal Membrane Oxygenation 359
as a bridge to cardiac transplantation.13 The results were not impressive. IABP and various
circulatory assist devices can also be used as a bridge to cardiac transplantation. Like ECMO,
IABP can be used as a bridge only for a short period. Probably we need more studies on
ECMO as a bridge to cardiac transplantation and more effective chronic circulatory support
system.

SUMMARY
■ Extracorporeal membrane oxygenation nowadays is commonly used modality to manage
critically ill cardiac and pulmonary patients. VA ECMO is reliable method to institute
systemic rescue perfusion in life-threatening cardiac low-output states.
■ Extracorporeal membrane oxygenation can be placed in various settings.
■ The use of ECMO is associated with many life-threatening complications.
■ If identified in time, these complications can be managed successfully.
■ Extracorporeal membrane oxygenation can be used as a bridge to cardiac transplantation
for short period only.

REFERENCES
1. Brown JL, Estep JD. Temporary percutaneous mechanical circulatory support in advanced heart
failure. Heart Fail Clin. 2016;12(3):385-98.
2. Lim HS, Howell N, Ranasinghe A. Extracorporeal life support: physiological concepts and clinical
outcomes. J Card Fail. 2017;23(2):181-96.
3. Ouweneel DM, Schotborgh JV, Limpens J, et al. Extracorporeal life support during cardiac arrest and
cardiogenic shock: a systematic review and meta-analysis. Intensive Care Med. 2016;42(12):1922-
34.
4. Raman L, Dalton HJ. Year in review 2015: extracorporeal membrane oxygenation. Respir Care.
2016;61(7):986-91.
5. Squiers JJ, Lima B, DiMaio JM. Contemporary extracorporeal membrane oxygenation therapy in
adults: fundamental principles and systematic review of the evidence. J Thorac Cardiovasc Surg.
2016;152(1):20-32.
6. Adult Extra Corporeal Membrane Oxygenation (ECMO). Policy and Guideline. RPAH; 2010.
7. Extra Corporeal Membrane Oxygenation (ECMO) in the Intensive Care Unit. St Vincent’s Hospital
Sydney ICU; 2010.
8. Marasco SF, Lukas G, McDonald M, et al. Review of ECMO (extracorporeal membrane oxygenation)
support in critically ill adult patients. Heart Lung Circ. 2008;(17 Suppl 4):S41-7.
9. Gokalp O, Besir Y, Eygi B, et al. Complications of cannulation in extracorporeal membrane
oxygenation. Ann Vasc Surg. 2015;29(1):164.
10. Tanaka D, Hirose H, Cavarocchi N, et al. The impact of vascular complications on survival of patients
on venoarterial extracorporeal membrane oxygenation. Ann Thorac Surg. 2016;101(5):1729-34.
11. Cheng R, Hachamovitch R, Kittleson M, et al. Complications of extracorporeal membrane
oxygenation for treatment of cardiogenic shock and cardiac arrest: a meta-analysis of 1,866 adult
patients. Ann Thorac Surg. 2014;97(2):610-6.
12. Mehta Y. Extracorporeal membrane oxygenation in ICU: prevention of nosocomial infections. In:
Kapoor PM (Ed). Manual of Extracorporeal Membrane Oxygenation (ECMO) in the ICU. New
Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2014. pp. 229-34.
13. Fukuhara S, Takeda K, Kurlansky PA, et al. Extracorporeal membrane oxygenation as a direct
bridge to heart transplantation in adults. J Thorac Cardiovasc Surg. 2018;155:1607-18.e6.
CHAPTER 42
Extracorporeal Membrane Oxygenation
for Toxicology
Samir Gami, Dipak Viradia, Haresh Vastarpara, Khushbu Vaghasiya

In today’s world we are losing many young lives because of severe myocardial and respiratory
depression caused by toxins taken for mainly suicidal agents. With use of ECMO till heart and
lung recover we can save many lives who have taken toxins as suicidal agents.
Acute poisoning is a common problem faced by physicians working in emergency units all
across the globe. A severe acute toxicity can be life-threatening or fatal. The death can either
be due to cardiovascular or respiratory failure. These toxicities can be accidental, homicidal,
or suicidal. Cardiac arrhythmias leading to fatal cardiac arrest, seizures, hypotension, and
respiratory depression are some of the features of acute poisoning and can lead to death of
the patient, if not treated in a timely manner. The poison profile varies all over the world; with
the causative agents being widely different from one part of the world to other. For example,
cardiotoxic drugs are common poisons in our country, while pesticides and other household
toxins are common in various other domains. Some commonly used patterns of toxicity which
are frequently encountered in clinical practice are overdose of medications, drug abuse,
ingestion of household or industrial chemicals, and poisoning by plant or animal toxins. In
our country, irrespective of the nature of the toxin, the patients affected are relatively young
and usually healthy with most of them being bread earner of their families.
Extracorporeal life support (ECLS) is increasingly being used as a bridge therapy in the
management of acute severe aluminum phosphide (ALP) poisoning-induced cardiac arrest or
cardiogenic shock. The basic principles in the management of intoxication includes decreasing
further absorption and increasing elimination of the toxin, administration of antidote, and
general supportive measures. The rationale of using extracorporeal membrane oxygenation
(ECMO) in such cases is to enhance the toxin metabolism and maintenance of adequate
cardiac output/oxygenation and tissue perfusion. Despite the evidence of favorable outcomes
with ECMO, there are no clear guidelines for the timeline for treatment with ECMO in the
existing literature. Hence, it is still not widely used clinically for ALP poisoning. Extracorporeal
Life Support Organization (ELSO) may help in resolving some of these issues since it supports
worldwide data collection for the use of ECMO in acute intoxication.
Chapter 42  Extracorporeal Membrane Oxygenation for Toxicology 361

INTRODUCTION
Acute severe poisoning is a global problem. The presenting symptoms in patients who come
to the emergency with toxin ingestion or inhalation range from mild-to-life-threatening
cardiovascular or respiratory failure. Immediate supportive measures and administration of
specific antidotes (if available) are first-line treatment strategies. It is usually effective but may
not be sufficient in cases of cardiovascular collapse due to life-threatening overdose. There has
been an increase in the mortality associated with acute poisonings over the last few decades.
This increase is irrespective of the nature of intoxication whether accidental or suicidal.
Extracorporeal membrane oxygenation or extracorporeal life support is a modality of
treatment similar to the heart-lung bypass machine, which pumps the blood through an
artificial lung and back into the circulation. Over the last few years, it is increasingly being
used to provide prolonged cardiac and respiratory support in refractory respiratory and
cardiopulmonary failure in children as well as in adults. However, adult data was not
encouraging until recently when venovenous ECMO (VV ECMO) showed encouraging results
during H1N1 pandemic as shown in conventional ventilatory support versus ECMO for severe
adult respiratory failure (CESAR) trial as well as with other reports. There is drastic rise in use
of ECMO in post-H1N1 pandemic in 2009.1
The most common cause of death in patients with acute poisoning is usually heart or lung
failure. Ventilator support using intubation has been lifesaving in some situations and has
improved chances of survival. There are various modes of treatment when the toxic substance
affects various other organs of the body. For example, renal replacement therapies when used
in cases of acute renal failure have shown encouraging results. In some cases, liver transplant
has been used as lifesaving measure in drug-induced fulminant liver failure. However, using
mechanical support as a means to support a failing heart due to acute poisoning has not
gained popularity so far. The basic purpose of ECMO is to provide enough oxygen to support
the failing heart and/or lung functions, while allowing time for the heart and lungs to heal from
the toxic injury. Thus, it is instituted as a bridge therapy, which provides some extra time until
specific therapy can be effective.
The patient may present with cardiovascular dysfunction, arrhythmia, or cardiovascular
collapse, if the poison in question is cardiotoxic. In some cases, this cardiovascular collapse
may even require a short-term support for the circulatory functions. This temporary support
will provide adequate tissue perfusion and help in the circulation of antidote as well as hepatic
detoxification over time. There are several modalities such as continuous cardiopulmonary
resuscitation, cardiopulmonary bypass (CPB), and intra-aortic balloon pump (IABP), which
have been used with varying rates of success. With technological advancement and better
outcomes with ECMO, emergency care physicians are now trying to explore newer indications
for use of ECMO in critical care patients.

CLINICAL EPIDEMIOLOGY
The poisoning substances can be broadly divided into three groups:2,3
1. Chemicals used in agricultural and industries
362 Section 2  Extracorporeal Membrane Oxygenation

2. Drugs and healthcare products


3. Biological poisons such as plant toxins and animal toxins.
The toxicity symptoms range from mild-to-severe and life-threatening cardiovascular and
respiratory dysfunctions.
Worldwide, an estimated three million cases of pesticide poisoning occur every year,
resulting in an excess of 250,000 deaths. Intentional and unintentional pesticide poisoning has
been acknowledged as a serious problem in many agricultural communities of low- and middle-
income countries, including China, India, Sri Lanka, and Vietnam. More than 400,000 victims
die due to accident (both natural and unnatural) in India and acute poisoning contributes
6.3% (approximately 26,000) deaths every year. However, suicide due to acute intoxication
leads to around 30,000 deaths every year. Pesticides are the most common substances used
in the developing world for poisoning and associated with high mortality.4 Conversely, the
toxins are different in the developed countries and they primarily are medications, especially
cardiovascular medications and illegal drugs of abuse. Overdose of certain drugs like analgesics,
tricyclic antidepressants, and antipsychotics can also cause cardiovascular collapse and
death.

WHY PATIENTS DIE WITH ACUTE INTOXICATION?


Acute intoxication with cardiotoxic drugs is associated with high mortality, which is around
12% worldwide. However, mortality associated with psychotropic drugs and noncardiotoxic
analgesics is around 4%.5 Severe acute intoxication leads to hemodynamic instability,
which may be accompanied by worsening of functions of other systems such as respiratory
depression, renal dysfunction, and seizures. This will further deteriorate cardiac functions and
a vicious cycle ensues, which will enhance the toxicity and may be fatal if corrective treatment
is not advocated in a timely manner. An immediate effort should be made to promptly assess
and maintain airway, support breathing, and optimizing circulation.
Difficult respiration may be assisted by short-term mechanical ventilatory support,
till the spontaneous breathing is established. Hypotension could be treated initially with
intravenous (IV) fluids. Vasopressor and inotropic agents can be used when blood pressure
does not increase even after adequate fluid resuscitation. Administration of specific antidote
may improve blood pressure. There are chances of arrhythmia with the use of inotropic
agents which may add to the cardiovascular toxicity. Antiarrhythmic administration is usually
avoided as the drugs themselves are proarrhythmic and some may have negative inotropic
effect. The other factors such as, acidosis, hypokalemia, hypomagnesemia, and hypoxia,
which may cause arrhythmia, should be investigated for and corrected promptly if found. With
improved understanding of pathology of shock, better monitoring techniques, and aggressive
supportive measures for hemodynamic stabilization, there has been significant progression in
management of toxin-induced cardiogenic shock in last few decades. Even then, the incidence
of cardiovascular collapse in patients with acute intoxication is as high as 17%. Sudden cardiac
death in a younger and otherwise healthy population is most likely due to poisoning.6 The
time of onset of cardiovascular symptoms after poison intake depends not only on quantity of
poison ingested but also on the toxicity profile and the type of toxin.
Chapter 42  Extracorporeal Membrane Oxygenation for Toxicology 363

CARDIOTOXIC TOXINS
Table 1 gives a comprehensive (but not all inclusive) list of poisons with cardiotoxic potential.
The pathogenesis of drug-induced cardiotoxicity involves systemic vasodilatation which leads
to hypotension due to hypovolemia followed by myocardial depression and dysfunction,
and in some cases life-threatening arrhythmias may also occur. Pesticides are widely used in
developing countries in rural and suburban areas. Being comparatively cheaper and easily
available make them ideal agents for self-harm. A severe poisoning with plant toxins may lead
to various arrhythmias and sometimes even complete heart block.

WHY EXTRACORPOREAL MEMBRANE OXYGENATION IN POISONING?


Extracorporeal membrane oxygenation is clinically indicated in patients with acute severe
heart or lung failure which does not respond to optimum conventional therapy. It is usually
considered if the mortality risk is more than 50% and definitely started in situations with
more than 80% mortality risk. Since these patients are relatively younger with less likely
comorbidities, a better outcome is usually expected once the toxin is entirely removed from the
body. Another benefit of ECMO is in redistributing the toxin and its metabolites from central
nervous system to other organs which facilitates the metabolism and speeds up the excretion
of toxin by improving hepatic as well as renal blood flow.
There are two different types of ECMO: Venoarterial (VA) ECMO and venovenous (VV)
ECMO. VA ECMO supports both heart and lung functions; whereas VV ECMO primarily
supports lung functions. So, depending upon the indication, one can use either type of
ECMO for treatment. Hence, the main indication of ECMO is in patients with such severe

Table 1: Toxins with cardiotoxic potential.


Drugs With membrane stabilizing activity (MSA): Others:
• Antiarrhythmic agents (Vaughan Williams class I) • Calcium channel blockers
• Beta-blockers • Meprobamate
• Dopamine and norepinephrine uptake inhibitors • Colchicine
(bupropion) • Cardiac glycosides (digoxin)
• Antiepileptics (phenytoin/carbamazepine) • H1 antihistaminics
• Antimalarial agents (quinine/chloroquine) • Beta-blockers (not associated with
• Polycyclic antidepressants (imipramine and MSA)
desipramine)
• Opioids
• Recreational agents such as cocaine
Pesticides Insecticides: Herbicides: Rodenticides:
• Organophosphates Paraquat • Aluminum phosphide
• Carbamates • Yellow phosphorus
• Zinc phosphide
Plant toxins • Aconite
• Taxus
Others • Carbon monoxide
• Cyanide
364 Section 2  Extracorporeal Membrane Oxygenation

cardiovascular dysfunctions or severe ventilation perfusion pathologies that are unlikely to be


resolved with conventional therapies.
There is no set of concrete guidelines to direct toward the appropriate time for the initiation
of ECMO in severely poisoned patients. The decision about initiation primarily depends on
ventilator setting and requirement of positive end-expiratory pressure (PEEP) and inspired
oxygen fraction (FiO2) of the patient. However, the rule of thumb is to initiate ECMO before
irreversible end-organ damage occurs, especially with poisons like organic hydrocarbons
which damages the lungs on aspiration and may lead to acute respiratory distress syndrome
(ARDS) without cardiovascular compromise.
Extracorporeal membrane oxygenation can be helpful in toxin-induced organ failure in the
following manner:

Bridge to Recovery
Cardiotoxicity with poisons where there is no specific antidote can be fatal even with
conventional treatments. VA ECMO can be used to support the cardiac function in patients
with severe cardiotoxicities like left or right ventricular dysfunction, persistent life-threatening
arrhythmias or even cardiac arrest.
Cardiovascular function starts recovering as soon as the concentration of the toxic
substance starts decreasing either due to metabolism or excretion. Hence, the duration of
ECMO treatment depends on several factors such as half-life of toxin, severity of poisoning,
severity of organ dysfunction at the initiation of ECMO, and recovery of cardiorespiratory
function. VA ECMO reduces cardiac oxygen consumption and provides both hemodynamic
and respiratory support as a bridge to recovery in poisoning.
In cases with compromised respiration while being stable hemodynamically, VV ECMO
can be used until the recovery of normal lung function. Toxicity with pulmonary toxins, such as
paraquat can also be supported with VV ECMO, which serves as a bridge to transplant in such
cases. Even with multiple drug intoxication or in cases where the nature of toxin is unknown,
ECMO support can be beneficial, if there is an evidence of cardiogenic shock.

Bridge to Antidote
Sometimes, the antidotes for some poisons may not be readily available either due to short
shelf-life or high cost. In such cases, ECMO can be used as a bridge therapy until the antidote
becomes available. It can be helpful in life-threatening arrhythmias or cardiovascular collapse.
For example, digoxin-specific antibody fragments (Fab) acts as antidote in digoxin toxicity and
rapidly improves the digitalis-induced arrhythmias and cardiac toxicity. However, nowadays,
digoxin poisoning is quite uncommon due to infrequent use of drug and also Fab fragments
are very expensive with limited shelf-life; ECMO can be used to support the patient until Fab
is administered.

Bridge to Toxin Elimination with Renal Replacement Therapy


Dialysis is an important modality of treatment, which is effective in removal of toxin from the
circulation. The decision of initiating dialysis depends on the molecular weight, protein binding,
Chapter 42  Extracorporeal Membrane Oxygenation for Toxicology 365
and volume of distribution of the toxin. Large molecular weight drugs are poorly dialyzed.
So far, around 142 dialyzable poisons have been identified. Acute salicylate poisoning can
be managed successfully with dialysis, which will remove substantial amount of salicylate.7,8
ECMO will buy time to initiate renal replacement and eliminate toxin.

Bridge to Transplant
As stated above, toxins such as paraquat which are likely to cause irreversible and rapidly
progressing pulmonary fibrosis can be supported with VV ECMO as a bridge to transplant.
Usually, it is not possible to immediately transplant lung either due to unavailability of viable
donor or to wait for clearance of toxin from the tissues. Sometimes, even VA ECMO can be
helpful as a bridge to permanent assist device in patients with persistent cardiac failure.

REVIEW OF LITERATURE
There is a lack of substantial data on the use of ECMO in patients with severe poisoning leading
to refractory cardiac failure or ARDS. So, one has to rely on the evidences obtained from a few
animal studies, case series, and case cohort studies. This warrants a careful interpretation of
results due to the potential for bias.

Drug Toxins
Most of the available data which describes the use of ECMO in acute poisonings is from the
trials conducted in western countries. Three different experimental studies using lignocaine,
desipramine and amitriptyline in dogs and swine, respectively has shown better outcome with
ECMO in comparison to the use of conventional treatment methods.9
An observational cohort study in six severely poisoned patients who received VA
ECMO shows better outcome in patients where ECMO was used for profound shock as
compared to use of ECMO for other indications. The toxic substances were propafenone,
chloroquine, a sclerotic agent, a tricyclic antidepressant, and diuretics.10 In another cohort of
17 patients, where ECLS was initiated for refractory cardiac arrest, stable ECLS was achieved
in 14 patients.11
A retrospective cohort analysis in two hospitals in France evaluated all poisoning patients
who presented to the hospital. There was a statistically significant favorable outcome (86%
vs 48%) in severely intoxicated patients with refractory shock or cardiac arrest, who were
managed with VA ECMO as compared to conventional management. However, as the number
of patients treated with VA ECMO in this cohort is small, result interpretation needs to be done
cautiously.12
Also, there are a number of case reports which shows successful management of drug
intoxication-induced refractory shock using ECMO. These included evidence of successful
ECMO support in acute intoxication of some drugs like digoxin, tricyclic antidepressants,
flecainide, beta-blockers, calcium channel blockers, bupropion, mepivacaine, and
methamphetamine. It included both adult and pediatric patients, all of whom were supported
with VA ECMO; though the time of initiation and duration of ECMO treatment are different in
366 Section 2  Extracorporeal Membrane Oxygenation

each case. Common complications reported were bleeding, hypotension, thromboembolism,


or minor neurological events.

Other Substances
There is not much evidence for the use of ECMO in severe intoxication with toxic substances
other than drugs such as pesticides, carbon monoxide, cyanide, and plant toxins. The literature
available is limited to case reports or case series with only few patients. These are commonly
used as poisons in developing countries leading to high mortality rates but as of now ECMO
is not easily available to this population, which may be a probable reason for underutilization
of ECMO.
Carbon monoxide rapidly binds to hemoglobin to form carboxyhemoglobin, leading
to decreased oxygen carrying capacity of blood. This causes tissue hypoxia and multiple
organ failure. Both VV and VA ECMO can be used to manage tissue hypoxia depending on
hemodynamic stability.
Aluminum phosphide, a commonly used pesticide is a deadly poison which causes
severe myocardial dysfunction, arrhythmia, and death. This poisoning has been successfully
managed with VA ECMO at different centers. In one single-center, retrospective study between
January 2011 and June 2016, a total of 107 cases with ALP poisoning were identified, out of
which 67 were categorized in high-risk category as per the criteria based on left ventricular
ejection fraction (LVEF), lactate level, and hypotension. The in-hospital mortality of patients
who received ECMO in addition to conventional treatment (n = 35) was compared to those who
received conventional treatment (n = 32) only. The use of ECMO in addition to conventional
treatment reduced the in-hospital mortality from 84.4% to 40%. In our institute at Unique
Hospital, Surat, Gujarat, we have used VA ECMO for severe form of aluminum phosphate
poisoning in 42 patients.

SUMMARY
The use of ECMO in acutely intoxicated patients with cardiorespiratory failure, unresponsive
to routine treatment is increasingly getting popular among intensivists as bridge therapy in
order to buy some time for toxin elimination. The available evidences in literature are limited
to case reports and case series, which may have reporting and publication bias. It is difficult
to perform a randomized trial since it is ethically unacceptable due to high mortality in non-
ECMO group.
Toxicology is a unique subject, as there are so many toxic substances available. As they say,
anything in excess is poison; so there is no dearth of existing poisons. Each toxin has a different
pharmacokinetic and pharmacodynamics profile. The main advantage with ECMO is that it
is useful in supporting hemodynamic functions, irrespective of the type of poison involved.
But, it should be kept in mind that the complications associated with ECMO itself may be life-
threatening, which can be minimized with expertise.
Even after many years, our knowledge regarding use of ECMO in severe acute poisoning
is still limited and many issues are not yet resolved. Some of these include the correct time
Chapter 42  Extracorporeal Membrane Oxygenation for Toxicology 367
of initiation of ECMO, cost-effective management, combining various modes of therapies,
prognostic factors during ECMO initiation, decision regarding the withdrawal of ECMO support
after improvement. Due to these reasons, ECMO is still an underutilized modality in both
developed and developing countries. All these issues can be addressed by further research.
Also, the data registry of Extracorporeal Life Support Organization (ELSO), the largest world
organization for ECMO, provides an exceptional platform for global data collection on the use
of ECMO in poisoning.

REFERENCES
1. Domínguez-Cherit G, Lapinsky SE, Macias AE, et al. Critically ill patients with 2009 influenza
A (H1N1) in Mexico. JAMA. 2009;302(17):1880-7.
2. Kolecki PF, Curry SC. Poisoning by sodium channel blocking agents. Crit Care Clin. 1997;13(4):829-
48.
3. Henry JA, Cassidy SL. Membrane stabilizing activity: a major cause of fatal poisoning. Lancet.
1986;1(8495):1414-7.
4. Jeyaratnam J. Acute pesticide poisoning: a major global health problem. World Health Stat
Q. 1990;43(3):139-44.
5. Mokhlesi B, Leikin JB, Murray P, et al. Adult toxicology in critical care: Part II: specific poisonings.
Chest. 2003;123(3):897-922.
6. Manini AF, Nelson LS, Stimmel B, et al. Incidence of adverse cardiovascular events in adults
following drug overdose. Acad Emerg Med. 2012;19(7):843-9.
7. Doolan PD, Walsh WP, Wishinsky H. Acetylsalicylic acid intoxication: a proposed method of
treatment. J Am Med Assoc. 1951;146(2):105-6.
8. Holubek WJ, Hoffman RS, Goldfarb DS, et al. Use of hemodialysis and hemoperfusion in poisoned
patients. Kidney Int. 2008;74(10):1327-34.
9. Freedman MD, Gal J, Freed CR. Extracorporeal pump assistance–novel treatment for acute
lidocaine poisoning. Eur J Clin Pharmacol. 1982;22(2):129-35.
10. Martin TG, Klain MM, Molner RL, et al. Extracorporeal life support vs thumper after lethal
desipramine OD (abstract). Vet Hum Toxicol. 1990;32:349.
11. Larkin GL, Graeber GM, Hollingsed MJ. Experimental amitriptyline poisoning: treatment of severe
cardiovascular toxicity with cardiopulmonary bypass. Ann Emerg Med. 1994;23(3):480-6.
12. Vanzetto G, Akret C, Bach V, et al. Percutaneous extracorporeal life support in acute severe
hemodynamic collapses: single centre experience in 100 consecutive patients. Can J Cardiol.
2009;25(6):e179-86.
CHAPTER 43
Extracorporeal Membrane Oxygenation and
Renal Replacement Therapy
Anand Raghunathan, Kesava Dev, Buddhika PJ Samaranayaka

INTRODUCTION
The extracorporeal membrane oxygenation (ECMO) research began in 1970s and was first
used in 1972.1 Since then, various technological improvements in design and components
of ECMO circuit have taken place. Also, better pathophysiological understanding of various
critical illnesses related to respiratory and cardiac ailments has opened the window for
ECMO use in critical care unit. In the recent years, ECMO has become a well-established
bridge intervention for initiation and management of acute respiratory failure with poor gas
exchange2 and/or acute circulatory shock secondary to cardiac failure or sepsis3 leading to
cardiac arrest and extracorporeal cardiopulmonary resuscitation (eCPR).4 It is also used as a
bridge therapy toward heart and/or lung transplant recipients awaiting surgery.5,6 The use of
ECMO has improved the chances of survival in such selective subset of critically ill patients
who otherwise would have died. However, use of ECMO is not without any complication and
some of the major complications associated with ECMO are bleeding, infection, hemodynamic
instability, air embolism, thrombosis, and organ dysfunction.7 Acute kidney injury (AKI) is one
of the most common complications with high risk of mortality.8

ACUTE KIDNEY INJURY IN EXTRACORPOREAL MEMBRANE OXYGENATION


Incidence of AKI in patients undergoing ECMO is high, ranging from 50% to 80%.9,10 Infact,
AKI can present even before the initiation of ECMO or present later on after its initiation and
at times necessitating the need for use of renal replacement therapy (RRT)with ECMO.11 Such
subset of patients has a very high mortality and ECMO with continuous renal replacement
therapy (CRRT) is an independent predictor of mortality even after controlling the independent
variables.12,13 Early use of RRT with ECMO is also a subject for debate and review. Nevertheless,
RRT is used in AKI associated with ECMO for various reasons.14 Critically ill patients have
positive extracellular fluid overload due to the initial overzealous fluid management as part of
resuscitation and the ongoing systemic inflammatory response syndrome (SIRS) secondary to
organ dysfunction and initiation of ECMO. These patients usually have significant metabolic
Chapter 43  Extracorporeal Membrane Oxygenation and Renal Replacement Therapy 369
derangements secondary to combination of multiple associated factors like low cardiac
output, tissue ischemia, poor tissue oxygenation, infection, and poor nutrition. Furthermore,
ECMO initiation changes the blood flow dynamics from pulsatile to nonpulsatile pattern,15,16
and causes hemolysis of blood elements in circuit leading to free circulating hemoglobin,
myoglobin,17 triggering of systemic inflammatory response, dysregulation of renin angiotensin
aldosterone axis, and downregulation of atrial natriuretic peptide (ANP) hormone. All these
factors contribute to fluid overload and metabolic derangement with higher incidence of AKI
with ECMO use.18 The incidence is reported to be around 50–80%. The risk of AKI increases
significantly necessitating need for RRT consideration in almost more than 50% of the
patients with AKI. The most common reason for use of RRT in ECMO patients is to undertake
ultrafiltration in order to remove the excess fluid;19 as positive fluid balance complicates the
recovery of organ function and retards the reversal of disease process and may thus decrease
the chances of patient survival.20 Use of RRT not only may help in reducing the fluid load,
but also may help to clear the inflammatory chemical mediators in circulation, to correct the
electrolyte imbalance and removal of certain excess unwanted solutes, toxins, and drugs.21
When to start the RRT in AKI with ECMO, which modality to use, and for how long is a
challenging debatable question. Yet some studies have advocated better outcomes with early
institution of RRT in AKI with ECMO22 and some have also advocated combining different
modalities for optimal results.

INDICATIONS FOR CONTINUOUS RENAL REPLACEMENT THERAPY ON ECMO12


■ Fluid overload
■ Metabolic derangements—acidosis, electrolyte imbalance mainly potassium increase
■ Raised urea and creatinine
■ Sepsis to remove inflammatory mediators
■ Removal drugs

CRITERIA FOR ACUTE KIDNEY INJURY DETERMINATION


■ RIFLE (Risk, Injury, Failure, Loss of Function, End stage Renal Disease, 2004
■ AKIN (Acute Kidney Injury Network), 2007
■ KDIGO (Kidney Disease Improving Global Outcomes), 2012
All the three methods have been utilized for identifying and grading of AKI and none are
found to be superior over the other. They have all been used with reliability in most of the
cases, although they are not perfect and exist with limitations.4,23 These have been discussed in
detail in previous chapters.

BIOCHEMICAL MARKERS
Urine output, serum creatinine, blood urea nitrogen, serum electrolytes, glomerular filtration
rate (GFR), fractional excretion of sodium (FENa) are routinely used to identify AKI and these
indicators are also used in the RIFLE and AKIN criteria for identification of AKI and its grading.
Other markers like fHb, plasma-free myoglobin, red cell distribution width, plasma/urine
370 Section 2  Extracorporeal Membrane Oxygenation

albumin, bilirubin, haptoglobin, plasma-free iron, and hepcidin are also used. Advanced
methods of fluorescence-based measured GFR, levels of syndecan 1, endocan and selectins
may be useful markers for glycocalyx degradation while plasma/urine F2 isoprostanes and
isofurans can be used to identify oxidative stress-related kidney injury.24

TYPES OF EXTRACORPOREAL MEMBRANE OXYGENATION


■ Venovenous (VV)—pulsatile flow
■ Venoarterial (VA)—less pulsatile/nonpulsatile flow.

BASIC UNDERSTANDING OF THE EXTRACORPOREAL MEMBRANE OXYGENATION


CIRCUIT
Zone A: Between patient venous drainage and ECMO centrifugal pump
Zone B: Between ECMO centrifugal pump and ECMO oxygenator
Zone C: Between ECMO oxygenator and ECMO outflow to patient (Fig. 1).

Zone A (Pre-pump)
This is a negative pressure area where blood flows from patient into the pump of ECMO circuit.
Any inflow or outflow connection to or from RRT circuit linked to Zone A increases the chances
for air entrainment leading to air embolism and in case of significant air entrainment can lead
to pump failure and ECMO would stop functioning. Similarly, any outflow connection from
Zone A to Zone C also endangers risk of air and clot delivery directly to the patient. In other
words, any connection to or from this zone has to be a close loop circuit without open port for
any access, unless the outflow part from this zone is connected to the Zone B with no risk of
air embolism.

Zone B (Between Pump and Oxygenator)


This is a positive-pressure zone and any leaks in the circuit will lead to significant blood loss.
Also, being a positive-pressure zone, this site cannot be used as an access route for any drugs
or fluids. However, connection of CRRT in this zone has many advantages. There is no risk
of air embolism. Also, there is no recirculation of blood or membrane oxygenation shunt
issues.

Fig. 1: ECMO circuit.


(ECMO: extracorporeal membrane oxygenation)
Chapter 43  Extracorporeal Membrane Oxygenation and Renal Replacement Therapy 371

Zone C (Postoxygenator)
This is also a positive-pressure zone but less so than Zone B and any leak here would also
lead to blood loss. Also, any outflow circuit connection from RRT at this point places risk of
embolism or clot delivery to the patient.

Connections for Cardiac Support


Zone B to Zone C/Zone C to Zone B.

MODES OF RENAL REPLACEMENT THERAPY25-28


■ Slow continuous ultrafiltration (SCUF)
■ Continuous hemofiltration—continuous venovenous hemofiltration (CVVH)/continuous
venoarterial hemofiltration (CVAH)
■ Continuous dialysis—continuous venovenous hemodialysis (CVVHD)/continuous
venoarterial hemodialysis (CVAHD)
■ Continuous hemodiafiltration—continuous venovenous hemodiafiltration (CVVHDF)/
continuous venoarterial hemodiafiltration (CVAHDF)

CIRCUIT COMPONENTS (ECMO WITH CRRT)14


■ Patient venous cannulation site [internal jugular vein (IJV)/femoral/right atrium (RA)]
■ Venous drainage circuit line (Bioline heparin coated to prevent coagulation)
■ Extracorporeal membrane oxygenation pump (centrifugal pump use to decrease trauma
to blood elements)
■ Extracorporeal membrane oxygenation oxygenator
(Hydrophobic membrane increases life span and less thrombogenic with better gas
exchange, air traps and with additional inlet and outlet port for priming, air vent, and measuring
transmembrane pressure gradients)
■ Continuous renal replacement therapy device (connected to ECMO circuit with inflow
circuit, filter, and outflow limb circuit)
■ Patient arterial cannulation site (femoral/aorta/carotid)
■ Ultrasonic flow sensor—to measure blood flow rate and detect air/gas/clot in circuit.

CONTINUOUS RENAL REPLACEMENT THERAPY CIRCUIT


The CRRT circuit includes the inflow line from ECMO, filter for hemofiltration (HF) or
dialysate, and the outflow line to the ECMO. Various positions exist for the placement of
the CRRT inflow and outflow lines and each has some advantages and disadvantages. Also,
it is to be noted that CRRT inflow line pressure limit is kept between −250 mm Hg and
+200 mm Hg; and outflow line pressure is kept between −50 mm Hg and +350 mm Hg. It is
important to understand the various possible areas in the ECMO circuit where the CRRT and
its circuit can be attached and these will be discussed subsequently in detail with advantages
and disadvantages (Fig. 2).
372 Section 2  Extracorporeal Membrane Oxygenation

Fig. 2: ECMO with CRRT.


(CRRT: continuous renal replacement therapy; ECMO: extracorporeal membrane oxygenation)

TYPES OF RRTS POSSIBLE ON ECMO25,26


■ Peritoneal dialysis (PD)
■ In-line hemofilter to ECMO circuit
■ Continuous renal replacement therapy use independent of ECMO circuit
■ Continuous renal replacement therapy attached on to ECMO circuit
■ Continuous renal replacement therapy with intermittent hemodialysis (IHD) on ECMO
circuit.

Peritoneal Dialysis26,29
Peritoneal dialysis use alone in patients with AKI on ECMO is an ineffective and slower means
to overcome removal of excess fluid and unwanted solutes. However, there is a possibility to
combine PD with CRRT in patients on ECMO with AKI. Such combined techniques of PD with
CRRT in patients with AKI on ECMO support have been undertaken in infants; especially,
ECMO use in postcardiac surgery infants or infants with respiratory distress syndrome,
sepsis, and shock. PD has been used effectively in combination with hemofiltration (HF)/
hemodialysis (HD) to achieve appropriate fluid balance goal strategy. PD is usually added
when hemodynamic instability exists. Low ECMO flow persists or the fluid status goals are not
achieved with HF/HD alone or abdominal compartment syndrome coexists with AKI. Not only
does it help in removing excess fluid and unwanted solutes from extracellular compartment,
but it can also have added advantage of obviating the need for additional vascular access and
relieving abdominal compartment overpressure. Further, during the recovery phase, when
removal of ECMO and CRRT lines are undertaken and if a further need for RRT is anticipated
so as to remove excess fluid or clear unwanted solute in AKI, then PD can still be kept and used
as means to provide RRT, thus overcoming the need for other more invasive vascular means to
institute CRRT (Fig. 3).

In-line Hemofilter to Extracorporeal Membrane Oxygenation Circuit30


Possible connections: Zone B to Zone C/Zone B to Zone A/Zone C to Zone A (Fig. 4).
Chapter 43  Extracorporeal Membrane Oxygenation and Renal Replacement Therapy 373

Fig. 3: PD with CRRT in ECMO patient.


(CRRT: continuous renal replacement therapy; ECMO: extracorporeal membrane oxygenation; PD: peritoneal
dialysis)

Fig. 4: In line hemofilter in ECMO circuit.


(ECMO: extracorporeal membrane oxygenation)

Position 1: Zone B to Zone A (Yellow) 1a—inflow to hemofilter; 1b—outflow from


hemofilter;
Position 2: Zone B to Zone C (Green) 2a—inflow to hemofilter; 2b—outflow from hemofilter;
Position 3: Zone C to Zone A (Black) 3a—inflow to hemofilter; 3b—outflow from hemofilter.
In patients requiring renal replacement therapy on ECMO, the easiest and quickest way
to achieve this is by placing a simple hemofilter in the ECMO circuit in Zone B, between the
pump and the oxygenator. Under the positive driving pressure of blood from the pump into the
hemofilter the process of ultrafiltration or hemofiltration is undertaken and excess fluid and
some unwanted solutes can be removed. This method is also cost-effective. If the outflow line
from the filter is connected back to the ECMO circuit before the pump (Zone A) this would lead
to recirculation of blood. This technique thus leads to shunting of blood from ECMO to the
hemofilter. To avoid this shunting of blood the outlet line from hemofilter can be connected
to the arterial line beyond the oxygenator, i.e. Zone C. However, this would mean risk of air
or clot delivery to the patient increasing organ injury risk; more so with venoarterial method
374 Section 2  Extracorporeal Membrane Oxygenation

than venovenous method of ECMO. Also, when connected from Zone B to Zone C with a
Quadrox D (PMP type) oxygenator there can be low driving pressure for blood through the
hemofilter, as there is a low-pressure gradient across the oxygenator or with use of Medtronic
Ave Cor 4500 (silicone membrane type) there can be a high resistance and significant pressure
drop across the oxygenator. When connections are placed such that blood flows from Zone B
to Zone A or Zone C to Zone A, then it must be ensured that it is a closed loop system, as any
open connection port here can lead to air embolism and pump can stop functioning with risk
of gas embolism to patient. However, with close vigilance to pump setting and ultrafiltration
volume status, slow continuous ultrafiltration or hemofiltration can be undertaken.
With this technique of in-line hemofilter, there is no mechanism to monitor the line
pressures or measure the actual blood flow into the hemofilter circuit and subsequently
measurement of the actual blood flow delivered to the patient. This is an obvious disadvantage.
However, placing an ultrasonic probe sensor on the arterial outlet line postoxygenator will
help in estimating the actual blood flow being delivered to the patient. Also, in this technique,
there is a difficulty in meticulous monitoring of the ultrafiltration volume, as it would mean
vigilant nursing care with need for more nursing staff to monitor the ultrafiltration volume,
though this could be the only means of determining the exact ultrafiltrate volume.
This technique needs the use of infusion pumps for control of dialysis fluid into the
filter, effluent fluid out of filter or additional of replacement fluid into the circuit as shown
in Figure 5 and these infusion pumps can lead to inaccurate delivery. Also, they offer some
resistance to flow of fluid in or out of the circuit. Furthermore, there is an increased risk of
clotting and rupture of filter membrane leading to decreased filter shelf-life.

Separate CRRT “Out of Line” and Independent of ECMO Circuit Use27,28


A separate CRRT independent of ECMO circuit connection is possible. However, this would
necessitate placing two vascular access sites in addition to the two sites used for ECMO.

Fig. 5: Components attached to and from hemofilter on “In-line hemofilter” with ECMO.
(DF: dialysis fluid; ECMO: extracorporeal membrane oxygenation; EF: effluent fluid; IF: infusion pump;
RF: replacement fluid)
Chapter 43  Extracorporeal Membrane Oxygenation and Renal Replacement Therapy 375

Fig. 6: CRRT independent of ECMO circuit.


(CRRT: continuous renal replacement therapy; ECMO: extracorporeal membrane oxygenation)

Also, this would mean increase complications pertaining to vascular cannulation especially
under the influence of heparin in circulation with higher activated partial thromboplastin
time (APTT) values than normal, leading to increase bleeding and also with an increased
risk of infection. Furthermore, vascular access sites, if used for CRRT purpose would limit the
availability of any cannulation sites for any future purpose.
The major advantage is that hemofiltration would be independent of ECMO flow or
pressures. Also, changes in the flow dynamics from pulsatile to continuous nonpulsatile flow
during ECMO may make the process of hemofiltration ineffective. Further, the circuit life is
directly dependent on the blood flow. Higher the blood flow into the circuit, longer is the life
span of the circuit. Lower blood flow is associated with thrombosis in the membrane circuit
decreasing the efficiency and life span of the circuit (Fig. 6).

CRRT Attached to ECMO Circuit31


Continuous renal replacement therapy can be attached directly to the ECMO circuit. The
major components in ECMO are the centrifugal pumps and the oxygenator. It is important to
know the various sites CRRT machine can be placed in the ECMO circuit and its implications.
We will discuss this in detail.

HEMOFILTRATION GOALS
■ Blood flow of 200–300 mL/min;
■ Clearance rate of 20–25 mL/kg/hr for RRT
■ High volume hemofiltration > 50 mL/kg/hr
■ Filtration fraction lower than 25%.

POINTS TO CONSIDER WHEN PLACING CRRT IN-LINE ECMO CIRCUIT FOR


EFFICIENCY OF FILTRATION
■ Extracorporeal membrane oxygenation cannula size
■ Extracorporeal membrane oxygenation blood flow and pressures
■ Continuous renal replacement therapy position in ECMO circuit
■ Continuous renal replacement therapy inflow and outflow line pressures
■ Ultrafiltration vs dialysis or combination of both
376 Section 2  Extracorporeal Membrane Oxygenation

■ Recirculation
■ Oxygenation membrane shunt
■ Air embolism risk
■ Anticoagulation to prevent thrombosis in circuit.
Attaching CRRT directly to the ECMO circuit helps in better clearance rate compared
to SCUF technique as used in in-line hemofilter technique discussed above. However, the
challenging aspects with use of CRRT with ECMO circuit are its appropriate position and
management of line pressures. It is to be noted that Zone A is a negative pressure and Zone
B is positive pressure and any change in the ECMO flow will also change the line pressures in
the CRRT circuit. Too low pressure will hamper the efficiency of filtration process in CRRT and
too high pressures beyond set limit will also stop the flow of blood hampering the efficiency
of filtration. One way of overcoming the problems of high-pressure alarms in CRRT circuit
is to inhibit the alarm or to decrease the ECMO blood flow. However, this can have clinical
implications on patient’s hemodynamics and tissue perfusion.
We will look into certain technical and clinical implications of placement of CRRT in ECMO
circuit.31

Position 1 (Zone A): Placing the CRRT in Pre-pump Circuit


(Used if the CRRT Return line pressure > +350 mm Hg)
This is a negative-pressure zone. This is advantageous for access line drainage to the hemo-
filter of CRRT and also there is no recirculation or membrane oxygenation shunt problem.
However, risk of air embolism exists if any access port is opened to air. Any excess air reaching
the pumps can thereby stop the pump and the functioning of ECMO. Further, there turn line is
also connected to negative pressure existing in the circuit and this will give low-pressure alarm
decreasing the flow of blood into the ECMO circuit. In order to improve the efficiency of filter
and also drainage into the ECMO, a clamp on this outflow line may be needed to overcome any
low-pressure alarm in circuit (Fig. 7).

Position 2 (Zone B): CRRT Line Connected between Pump and Oxygenator
(CRRT inflow pressure < + 200 mm Hg; return line pressure < +350 mm Hg)
However, connection of CRRT in this zone has many advantages. There is no risk of air
embolism. Also, there is no recirculation of blood or any membrane oxygenation shunt issues
altering the oxygenation of blood delivery to patient. However, the inflow line and outflow are

Fig. 7: CRRT placed in Zone A of ECMO circuit.


(CRRT: continuous renal replacement therapy; ECMO: extracorporeal membrane oxygenation)
Chapter 43  Extracorporeal Membrane Oxygenation and Renal Replacement Therapy 377
connected to a positive pressure and this would mean decrease in the flow of blood to the filter
and this would also affect the efficiency of filtration process if the pressure in the inflow or
outflow circuit is too high (Fig. 8).

Position 3: CRRT Line between Zone A to Zone B


(Used if CRRT inflow pressure is >+ 200 mm Hg)
Here the blood flows into the filter from negative-pressure zone and any access ports, if used
in this inflow line to filter can lead to air embolism. However, there are some advantages in this
circuit as the return line is into a positive-pressure zone, and there is no risk of recirculation or
membrane oxygenation shunt (Fig. 9).

Position 4: CRRT Line between Zone A and Zone C


There is risk of air/gas embolism or clot delivery to the patient and also the closed loop must
be maintained without any inlet access ports (Fig. 10).

Fig. 8: CRRT placed in Zone B of ECMO circuit.


(CRRT: continuous renal replacement therapy; ECMO: extracorporeal membrane oxygenation)

Fig. 9: CRRT with ECMO between Zone A to Zone B.


(CRRT: continuous renal replacement therapy; ECMO: extracorporeal membrane oxygenation)
378 Section 2  Extracorporeal Membrane Oxygenation

Position 5: CRRT Line between Zone C and Zone B


Flow across the oxygenator is high reducing its shelf-life and also there is increased risk
for thrombosis necessitating appropriate and regular anticoagulation check. However,
the oxygenator here acts as an additional trap for any air/gas in circuit before delivering
blood back to the patient. Recirculation of blood back into the circuit is an issue with this
design (Fig. 11).

Position 6: CRRT Line between Zone B and Zone C


There is an increased risk of air embolism or clot delivery to patient, especially if VA ECMO
is used and also there is risk of shunting of deoxygenated blood being delivered to patient
bypassing the oxygenator (membrane oxygenation shunt). This may decrease the oxygen
delivery to the patient and this could be of concern, especially if patient oxygenation status
is already poor. The performance of the pump can decrease over time due to high-pressure
circuits and may need higher pump flow. However, life span of the circuit oxygen at or maybe
prolonged with the use of this connection (Fig. 12).

Fig. 10: CRRT with ECMO between Zone A to Zone C.


(CRRT: continuous renal replacement therapy; ECMO: extracorporeal membrane oxygenation)

Fig. 11: CRRT with ECMO between Zone C to Zone B.


(CRRT: eontinuous renal replacement therapy; ECMO: extracorporeal membrane oxygenation)
Chapter 43  Extracorporeal Membrane Oxygenation and Renal Replacement Therapy 379

Fig. 12: CRRT with ECMO between Zone B to Zone C.


(CRRT: continuous renal replacement therapy; ECMO: Extracorporeal membrane oxygenation)

Fig. 13: CRRT with IHD use in ECMO.


(CRRT: continuous renal replacement therapy; ECMO: extracorporeal membrane oxygenation; IHD: intermittent
hemodialysis)

CRRT with IHD use in ECMO32 (Fig. 13)


Intermittent hemodialysis is a well-established technique in chronic renal failure for rapid and
quicker means to achieve clearance of excess water, unwanted solutes, correction of acidosis
and arrhythmias due to electrolyte imbalance, especially hyperkalemia. However, its initiation
causes hemodynamic instability and often is not the technique used in critical care setting,
when renal replacement therapy is required for AKI. Patients in ECMO are also more prone to
hemodynamic and metabolic changes, especially when suddenly a rapid means of clearance
of water and solutes are undertaken, as is the case if IHD used. However, fewer studies exist in
the literature as case reports, where IHD has been combined with CRRT on ECMO; especially
in refractory hyperkalemia and uremia uncorrected with CRRT alone when on ECMO after
use of all possible medications to correct hyperkalemia. Although successful weaning from
ECMO with recovery from AKI was achieved in such patients, yet evidence for its use needs
more research.
380 Section 2  Extracorporeal Membrane Oxygenation

POSSIBLE COMPLICATIONS
■ Bleeding: ECMO and CRRT increase the risk of bleeding mainly because of additional
vascular access use and also if any anticoagulants are used to prevent thrombosis in the
circuit.
■ Air embolism: Risk of air embolism exists, if any access port is open in Zone A or if CRRT
placed in Zone A. This can lead to pump failure. Further, if the outflow path by passes the
oxygenator and is connected to Zone C directly, then there is a risk of air or clot delivery to
the patient.
■ Recirculation: This phenomenon can happen, if the outflow circuit is connected from Zone
B or Zone C to Zone A or from Zone C to Zone B where by instead of delivering the blood to
the patient the blood recirculates back into the ECMO circuit.
■ Membrane oxygenator shunt: This can happen if the outflow blood bypasses the oxygenator
without getting oxygenated and is directly connected from Zone B to Zone C or from Zone
A to Zone C. This would mean some shunting of blood which is deoxygenated and at times
can lead to oxygenation problems when patient is hypoxemic.
■ Thrombosis: Risk exists if anticoagulation not used in the circuit over days of use. Low blood
flow into the filter or circuit too can lead to thrombosis. Also, recirculation of blood flow
into the filter can increase the chance of thrombosis and decrease shelf-life of filter.

CONTINUOUS RENAL REPLACEMENT THERAPY AND ANTICOAGULATION


Owing to the bioline coating in oxygenator and cannula tubing which prevent thrombosis,
routine anticoagulant use may not be necessary; and in case of any contraindication for
systemic anticoagulation the circuits can be used for few days without anticoagulation.
However, unfractionated heparin is frequently used to prevent thrombosis in the circuit and
also to increase the shelf-life of the filters. If citrate is used as an anticoagulant33 it must be
used only for the CRRT circuit and not the ECMO circuit. It provides good anticoagulation and
increases the shelf-life of the oxygenator. Also, additionally there is less need for transfusion
and less inflammatory response with citrate use as an anticoagulant. It is useful in conditions,
where anticoagulation is needed and that heparin is contraindicated.

INDICATION AND CONTRAINDICATION OF CITRATE USE


■ Indication of citrate use—High bleeding risk patients/thrombocytopenia/recent surgery/
coagulopathy.
■ Contraindication citrate use—hepatic failure/massive blood transfusion.

IMPLICATIONS OF CRRT POSITION IN ECMO CIRCUIT


The implications of CRRT position in ECMO circuit is given in Table 1.

MANAGEMENT OF PRESSURE ALARMS IN THE CIRCUIT34


If there is any high-pressure alarm triggered in the inflow line of the CRRT machine (in Zone B),
then the inflow line may be connected from pre-pump (Zone A), which actually is a negative-
Chapter 43  Extracorporeal Membrane Oxygenation and Renal Replacement Therapy 381

Table 1: Implications of CRRT position in ECMO circuit.


CRRT position in ECMO Membrane
(Inflow/outflow) Air embolism risk oxygenation shunt Recirculation Alarms
Zone A to A Yes No Yes Low pressure
Zone B to B No No No High pressure
Zone A to B Yes No No Low pressure (Inflow)
Zone A to C Yes Yes No Low pressure (Inflow)
Zone C to B No No Yes High pressure (Outflow)
Zone B to C Yes Yes No High pressure (Inflow)
(CRRT: continuous renal replacement therapy; ECMO: extracorporeal membrane oxygenation)

pressure zone. And, if still high-pressure alarm exists in the inflow line, then the only option
may be to decrease the flow into the CRRT. This may, however, hamper the efficiency toward
removal of excess water and unwanted solutes clearance for which CRRT was instituted in
the ECMO circuit. Any high pressure in the outflow circuit line of CRRT means decrease in
the flow of blood in the circuit and also decreasing the effectiveness of filtration. This can be
overcome by connecting the outflow line into the pre-pump circuit (Zone A) which is at a
negative pressure. If this connection leads to low pressure alarm then a clamp can be placed
on this line to slightly increase the pressure in the line without triggering the alarm. However,
if still low-pressure alarm persists then only option may be to decrease the CRRT blood inflow.
This again may hamper effectiveness of filtration and the very purpose of CRRT use for renal
clearance of excess water and unwanted solutes may be defeated.

CONTROVERSIES OF ECMO WITH RENAL REPLACEMENT THERAPY


Timing of Initiation of Continuous Renal Replacement Therapy35
Some studies have shown benefit in patient survival with AKI, when CRRT is initiated early
on when on ECMO.22 The main advantage is to remove excess fluid and also correct initial
metabolic derangement. However, a meta-analysis done on the early vs late initiation of CRRT
for AKI in ECMO patients did not show any difference in terms of renal function recovery,
CRRT dependence, duration of CRRT, renal recovery time, number of ventilatory days, ICU
stay, hospital stay or mortality, or survival benefit.35,36

Duration of Continuous Renal Replacement Therapy12,30


Some studies comparing use of CRRT with ECMO showed less ECMO duration need for patient.
This evidence was in contrast to many studies where CRRT use in ECMO prolonged the ECMO
duration in patient. Hence, impact of CRRT with ECMO on ECMO duration is inconclusive and
more vigorous research is needed to conclude on it.

Modality of CRRT and Outcome on ECMO29,31,32


Continuous renal replacement therapy incorporated into the ECMO is the most common
method used along with ECMO, primarily for hemofiltration. Yet in certain situations
382 Section 2  Extracorporeal Membrane Oxygenation

combination methods of modes, e.g. hemodiafiltration have been used to improve outcome
when one of the modalities was found to be ineffective. Also, combination of techniques like
CCRT with IHD or PD has been used to increase the efficiency of hemofiltration process.
However, some studies have used CRRT independent of the ECMO circuit with better outcome.
No single modality technique is found to be superior to other, though the choice is more on
the institutional practice norms based on target set for patient’s hemodynamic and metabolic
status.

Position of CRRT in ECMO Circuit31


The most common and safest site for placement of CRRT with ECMO is between the pump
and oxygenator (Zone B—post-pump and preoxygenator). This has many advantages as
described above. However, this is a high-pressure circuit and may need management at times
of the high-pressure alarms in the circuit, which could alter the blood flow delivery to patient.
Modifications of connections to circuit maybe needed at such times. However, various other
CRRT positions on ECMO have been well described in this chapter and they have also been
used effectively.

Cannula Size and its Impact on CRRT with ECMO36


Very few studies have been published in literature concerning the size of cannula use and
ECMO outcome. In one such study, no significant difference was seen between smaller
cannula groups (14–15 Fr VA femoral cannula) versus larger cannula group (16–21 Fr).
No statistically significant difference was seen in ECMO flow, weaning from ECMO or survival
rate. However, smaller cannula group had a lower value for ECMO blood flow. The only
statistically significant difference noticed were lesser ECMO duration need and lesser lower
limb ischemia complication seen in the smaller cannula group.

SUMMARY
The CRRT with ECMO for critically ill patients despite being challenging could be promising
for patient survival, with better understanding of the complexity involved in establishing,
maintaining and weaning at the optimal time. More research and data would help in providing
answers to various challenges involved in it.

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13. Lin CY, Chen YC, Tsai FC, et al. RIFLE classification is predictive of short-term prognosis in
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14. Chen H, Yu RG, Yin NN, et al. Combination of extracorporeal membrane oxygenation and
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17. Barrett CS, Jaggers JJ, Cook EF, et al. Pediatric ECMO outcomes: comparison of centrifugal versus
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removal in neonates requiring extracorporeal membrane oxygenation after cardiac surgery. J Extra
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extracorporeal membrane oxygenation in patients treated in medical intensive care unit: technical
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30. Blijdorp K, Cransberg K, Wildschut ED, et al. Hemofiltration in newborns treated with Extracorporeal
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31. Ostermann M, Connor M Jr, Kashani K. Continuous renal replacement therapy during extracorporeal
membrane oxygenation: why, when and how? Curr Opin Crit Care. 2018;24(6):493-503.
32. Tijssen JA, Filler G. When CRRT on ECMO is not enough for potassium clearance: a case report.
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33. Shum HP, Kwan AM, Chan KC, et al. The use of regional citrate anticoagulation continuous
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35. Paek JH, Park S, Lee A, et al. Timing of initiation of sequential continuous renal replacement therapy
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36. Kim J, Cho YH, Sung K, et al. Impact of cannula size on clinical outcomes in peripheral venoarterial
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CHAPTER 44
Nutrition in Extracorporeal
Membrane Oxygenation
Ruchira Khasne, Leena Bhangale, Mansi Dandnaik

INTRODUCTION
Extracorporeal membrane oxygenation (ECMO) is an advanced vital organ support system
which provides cardiorespiratory support to patients who have life-threatening respiratory or
cardiovascular failure. Venoarterial ECMO (VA ECMO) is used in patients with cardiovascular
failure and venovenous ECMO (VV ECMO) is used in respiratory failure with intact cardiac
function. These patients are the most critical patients in intensive care unit (ICU) and are often
unable to meet their calorie–protein requirements for prolonged period of time because of
various reasons. These patients often have increased metabolic activity with negative nitrogen
balance due to protein catabolism and insulin resistance ultimately resulting in more severe
calorie and protein deficit. This leads to muscle wasting with adverse outcomes.1 Nutrition
guidelines have been published for the neonates supported with ECMO long back2 but still
there are no established guidelines for the adults on ECMO. The Extracorporeal Life Support
Organization (ELSO) guidelines have stated that similarly to all critically ill patients, “full
caloric and protein nutritional support is essential to the patients on ECMO”.3 Thus, this group
of patients should be investigated separately and guidelines should be formulated. Till date,
nutrition guidelines applicable for general critically ill population are applicable to these
patients.4 An interdisciplinary approach with specific nutrition set of protocols, screening
program, and frequent assessments of nutritional status targeting to achieve the nutrition
goal are warranted to have a better long-term outcome. Thus, appropriate nutrition care plan
should be customized to each ECMO patient based on his or her state of critical illness for
betterment of outcome.

FACTORS AFFECTING NUTRITIONAL SUPPORT ON ECMO


Adequate nutrition delivery during ECMO is feasible, but there are various factors, which
actually preclude us to deliver adequate nutritional support leading to calorie and protein
deficit. However, as per a recent retrospective survey of 203 patients on ECMO, those with
severe organ failure have received inadequate energy and proteins compared to less severe
386 Section 2  Extracorporeal Membrane Oxygenation

organ failure and about one-third of patients were underfed (28.3%).5 They observed that there
is not much difference in ICU and 6-month survival of patients with inadequate energy or
protein intake. Thus, impact of underfeeding is yet to be defined. Underfeeding in ECMO is
still common, as quoted in a recent study by MacGowan L et al.5 Further prospective studies
are required to determine optimal feeding in these patients. Various factors, which affect
adequacy of nutritional support, are as follows:
■ Hemodynamic instability and vasopressor support: Extracorporeal membrane oxygenation
patients are severely ill and are often hemodynamically unstable requiring high doses of
vasoactive agents (especially in VA ECMO). As a result, splanchnic circulation is shunted,
which ultimately affects absorption of nutrients. Agents like epinephrine, dopamine,
and vasopressin decrease gastrointestinal (GI) blood flow, whereas norepinephrine,
dobutamine, and milrinone minimally affect GI blood flow. In clinical practice, multidrug
combinations and doses of these vasoactive agents make intestinal ischemia more difficult
to predict. Commencement of early enteral nutrition (EEN) is still a controversy because
of the risk of GI hypoperfusion and other complications such as abdominal distention due
to depressed peristalsis and mesenteric ischemia. EEN has been suggested and is feasible
as per the recently published ESICM clinical practice guidelines.6 ECMO has advantages
in improving blood gases, lowering down intrathoracic pressures mainly in VV ECMO, and
hemodynamic unloading in VA ECMO which in fact provides better circulatory support
as well as splanchnic perfusion.7,8 Authors should differentiate here between adults and
pediatric patients.
Thus, from the available evidences and consensus, vasopressors are not an absolute
contraindication to initiate EEN, but apparently, it needs careful monitoring. Principles
applicable to critically ill unstable patients hold true even for ECMO patient.9
– Consider for starting EEN when patient is on stable or decreasing dose of vasopressor.
An absolute dose of vasoactive agent is not defined to initiate EEN.
– Trophic feeding or gradual increase in nutrition is probably best strategy for this
population.
■ Heavy sedation and use of steroids: Sedative agents and steroids hamper gastric emptying
causing high gastric aspirate and further delay in initiation of EN on ECMO patients.
Prokinetics such as metoclopramide or erythromycin can improve gastric emptying and
helps to tolerate EN. Sedative agents like propofol provide nonprotein energy. When it
is used in infusion form for longer duration, it has been observed that the lipid content
of total nutritional therapy is exceeded. Situation is exacerbated when the patients are
also volume restricted with prescription of less formula feed creating a protein deficit. To
avoid this problem noncalorie-based sedation should be preferred. However, there is no
significant impact on GI intolerance.10
– Prokinetics such as metoclopramide or erythromycin should be added to improve GI
motility.
– Noncalorie-based sedation should be preferred.
■ Limitations of initial nutritional assessment and monitoring: Adequate nutrition is must
to maintain metabolic needs. Routinely calculation of energy requirement is done by
Chapter 44  Nutrition in Extracorporeal Membrane Oxygenation 387
weight-based predictive equations or by indirect calorimetry (IC). The technique of IC
calculates oxygen (O2) consumption and production of carbon dioxide (CO2). Measuring
IC for the patient on ECMO is challenging. We need to measure gas exchange via
membrane lung and native lung and also the impact of recirculation.4 Recirculation
makes the calculation even difficult by underestimating both the carbon dioxide and
oxygen exchange across the membrane lung. Varying cardiac output, thoracoabdominal
compliance, and resulting changes in state of intravascular blood volume also affect
measurement of IC.
■ Two studies demonstrated possible methods for measuring IC. In one, they measured
energy expenditure (EE) of patient’s lung by routine method via ventilator and then
additionally metabolic cart was attached to the membrane lung of ECMO circuit. For the
final calculation, all numbers are then added together and put into Wier equation for
final calculation.11 It is time-consuming method and this adaptor to connect metabolic
cart to the ECMO circuit is not available elsewhere. An alternative described method is
measurement of gas exchange using IC at the patient’s lung but instead of connecting IC
to the ECMO circuit, blood gas analysis was done from blood collected before and after
membrane oxygenator. O2 and CO2 content is then calculated using reference equation.
The energy expenditure was determined using Weir’s equation.12 In view of constantly
changing blood flow rates during ECMO run, EE cannot be static, which may eventually
influence the measurements. So both these protocols require prospective validation. In
absence of nutritional guidelines for ECMO patient, weight-based calculation same as
critically unwell patient should be considered.
– Indirect calorimetry is gold standard to estimate energy requirement but has its own
limitations on ECMO patients.
– Till robust guidelines are not defined, weight-based calculations similar to other
critically ill patients are applicable to this population.
■ Impact of systemic inflammation: Initiation of ECMO (VA ECMO) in itself can cause
inflammatory changes on GI microvasculature leading to altered GI motility, permeability,
and bacterial translocation, which further worsens sepsis and MODS delaying in initiation
of EN. Many recent studies have shown that EEN is well tolerated in both VA and VV ECMO
under appropriate supervision and incidence of intolerance is not different between both
the groups.10
– Early enteral nutrition can be initiated, irrespective of mode of ECMO.
■ Impact of large volume resuscitation: Mainly in VV-ECMO, often large volumes fluid
resuscitation is done to maintain high flow rates which cause generalized edema,
particularly in the gut reducing nutrient absorption and GI motility.10 Besides that, large-
volume resuscitation compromises the net volume of EN resulting in inadequate nutrition
to maintain optimum cumulative fluid balance. This modification mainly compromises the
protein part of enteral feeding as routinely used commercially available enteral formulas
are rich in energy with low protein content.
– When large volume fluid resuscitation is needed, nutritional formula with high protein
content is preferable.
388 Section 2  Extracorporeal Membrane Oxygenation

Causes of Frequent Interruptions5,13,14


The most frequent causes for interruption of feeding are medical procedures followed by
sluggish gastric motility. MacGowan et al.5 observed 203 patients of ECMO and reported that
39.1% of patients had interruptions due to procedures. Other causes such as GI intolerance
(22.8%), inability to gain access or mechanical complications due to feeding (15.2%), vomiting
(10.3%), high gastric residual volume (GRV) (5.4%) abdominal distension and constipation
(6.5%), gastrointestinal bleed or blood in aspirate (2.7%), feeding tube accidental removal
(2.2%) are observed. There are some rare causes like high stool output (0.5%), mechanical
complications like inability to insert feeding tube, tube accidental removal, blocked tube, and
hyperglycemia causing delay are documented.
■ Vigilant monitoring of GI intolerance to minimize feeding interruptions should be included
in nutrition protocol.
■ Loss of nutrients on extracorporeal membrane oxygenation circuit: There is a possibility
of loss of nutrients on ECMO circuit but its impact on outcome is less well studied. In
the intensive care patients requiring extracorporeal therapy, nutrients lost due to the
inflammation caused by the membranes should be considered. While replacing nutritional
support, the replacement of nutrients lost in the circuit should be included and modulate
the inflammation.15

Timing to Initiate
There is very limited data regarding the optimum timing to initiate EN in this group of patients.
Many times these patients are hemodynamically unstable and are on high doses of vasopressors,
withholding or delaying of EN is the preferred option over many years. EEN has been suggested
and is feasible as per the recently published ESICM clinical practice guidelines 2017,6 although
more RCTs or prospective cohorts are needed to have a strong evidence. Several observational
studies have shown that commencement of EN within 24 hours of starting ECMO is safe and
feasible with rare adverse events.5,10,14 Recent retrospective observational study comparing
early EN (within 2 days) vs delayed (3 days or more) in patients with cardiogenic shock on VA
ECMO, observed that early EN is not harmful but have lower in-hospital mortality and 28-day
mortality compared to delayed EN.16
■ Commencement of EN early within 24 hours of ECMO initiation is safe and feasible with
rare adverse events.

ROUTE OF ENTERAL NUTRITION


Nasogastric route is the most common route preferred as per available studies to deliver EN
on ECMO.4,14,17 It is easy to commence and less time consuming. The next preferred route is
jejunal route. Centers, which are well equipped with bedside jejunal tube placement, post
pyloric feeding is preferred. However, it is difficult to place and often takes longer time to
achieve.4 It is considered in patients with higher GRVs to prevent aspiration. High GRV can
be managed as per institutional policies. Use of prokinetic agents to improve GI motility such
as metoclopramide or erythromycin has been recommended.4 When EN cannot be tolerated,
then PN should be initiated either partially to supplement EN or as total parenteral nutrition.5
Chapter 44  Nutrition in Extracorporeal Membrane Oxygenation 389
But in ECMO patients, PN should be given with caution as lipid molecules can infiltrate the
oxygenator and cause problems.4,18 New-generation membranes do not have this problem but
requires close monitoring of ECMO circuit with monitoring of triglycerides (TG) levels. If TG
levels more than 3 g/L, lipid-free PN should be considered. Available data shows the incidence
of PN to be between 4% and 30% for ECMO patients, given either alone or in combination
with EN.4
■ Nasogastric route is the preferred route for EN due to its ease, simplicity, rapidity and is
well tolerated in most of the patients on ECMO.

DOSE
The optimal dose of caloric and protein requirements in the critically ill patients is unknown.
There is still uncertainty whether to match caloric intake with EE or to have less than EE during
the early phase.19 This holds true for ECMO patient. Nutrition risk scoring tools are designed as
per Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral
Nutrition (ASPEN).20 They are based on physiology and age of the patient. In ECMO patient’s
physiology is manipulated and mostly these patients are of younger age group, which may
underestimate their actual need. Thus, an individualized nutritional support regimen should
be provided.
■ The optimal dose of EN is difficult and individualized nutritional support regimen should
be provided. Optical dosing of EN is difficult in ECMO patients.

CALCULATION OF ENERGY AND PROTEIN TARGETS


Assessment of optimum calories and proteins, though difficult but most important step, has
yet not been defined in this group. But it should be calculated and modified over the period
of time as the dynamics of ECMO patient varies. Thus, energy and protein’s targets should be
adjusted and most appropriate feeding regimen should be implemented to achieve the target.

Energy
Guidelines have suggested to calculate energy requirement either by IC or by a weight-
based predictive equations. As per the available guidelines, IC is considered as the first-line
method for determining EE in critically ill adults.20,21 However, its use is not widespread due to
associated cost, it is time consuming, require technical skills, issues of calibrations, and cannot
be performed in certain patients with high FiO2.
Hence, predictive or weight-based equations are routinely used to determine energy dose.
Commonly used predictive equations like Harris–Benedict’s equation, Ireton Jones, etc. have
failed to asses EE and protein requirements accurately. There are several equations described
in literature, which are with specific weight calculations or validated for specific group of
population. These equations also have their own limitations. The correct equation should
be chosen for specific population to have a validated result. Available guidelines for general
critically ill patients should be followed to these patients till nutrition guidelines for ECMO are
not published. IC where suitable or weight-based equations such as 20–25 kcal/kg of actual
body weight in the intensive phase (as mentioned in Table 1) should be prescribed calories
390 Section 2  Extracorporeal Membrane Oxygenation

to the patients on ECMO followed by 25–30 kcal/kg BW/day in the recovery phase.21 60–70%
of prescribed energy should be provided by carbohydrates and rest by lipids and calories
obtained by proteins should not be included in calculations. In early phase of critical illness,
excess of calories may be associated with less favorable outcome. Cumulative energy and
protein balance should be calculated. It should be done daily ideally or at least twice per week
during ICU stay. Achievement of 80% of estimated target energy or 70% of measured energy
targets is associated with improved outcome in critically ill ICU patients and even it applies to
those receiving ECMO.20,22 Thus, nutritional protocols should be implemented to achieve the
target calories. Additional energy in the form of dextrose-containing fluids and lipid-based
medications such as propofol and citrate should also be considered while calculating energy
as failure to do so may lead to overfeeding.20
■ Available guidelines for critically ill patients should be followed until specific guidelines for
ECMO patients are developed. IC where available or weight-based equations ranging from
20 kcal/kg to 25 kcal/kg should be prescribed calories to the patients on ECMO.
■ Nutrition therapy should be adapted as per the course of the disease.

Protein
Proteins are most important for wound healing, immunity, and lean body mass. Critically
ill patients generally require higher amount of proteins, which cannot be fulfilled by routine
enteral formulas with high nonprotein calories. For critically ill patients, 1.2 g/kg/day is the
recommended protein target whereas obese, trauma, and burn patients require up to 2.5 g/
kg/day proteins.20 Adequate amount of protein delivery helps in reduction of skeletal muscle
wasting with improved physical function in the recovery and post ICU phase. Proteins like
albumin, C-reactive protein (CRP), etc. cannot be used to monitor the adequacy of protein
intake and are not recommended. Efforts should be done to achieve >80% of the prescribed
protein targets.20 Target recommendation for protein intake range from 1.52 g/kg/day to 2 g/
kg/day and higher, i.e. 2–2.5 g/kg/day in recovery phase of ECMO, obesity and trauma patients
(as mentioned in Table 1).

MONITORING THE ADEQUACY OF NUTRITION AND ITS LIMITATIONS


Underfeeding and overfeeding, both are detrimental for the outcome of critically ill adults.
Monitoring includes clinical parameters related to GI tolerance to enteral feeds by assessment
of GI dysfunction at least twice daily. Delivery of the energy and substrate may be best performed
by computerized system. The system should also include the number of calories that are

Table 1: Recommended target doses of energy and protein.


Recommended target Special situations
Energy (Initial phase) 15–20 kcal/kg ABW/day
(Recovery phase) 20–25 kcal/kg ABW/day
Protein (Initial phase) 1.5–2 g/kg/day
(Recovery phase) 2–2.5 g/kg/day Obese, trauma, and burn patients
(ABW: adjusted body weight)
Chapter 44  Nutrition in Extracorporeal Membrane Oxygenation 391
provided by sedatives (lipids) and drug dilution fluids (glucose).23 Other monitoring methods
include laboratory variables. Classical serum protein markers such as albumin, prealbumin,
transferrin, etc. are of limited value due to acute inflammatory response by ECMO circuits and
critically ill state.20 Similarly serum electrolytes, liver function tests, and inflammatory markers
are also barely able to guide us. Monitoring of energy expenditure and body composition is
done by the help of IC and bioimpedance analysis, respectively. Ultrasound is an emerging
tool for the measurement of muscle mass and to determine muscle mass changes due to ease
of use and availability. CT scan also provides precise quantification of skeletal muscles and
adipose tissues.20,23 Both the tools are in its infancy requiring validation for use, but may be of
value in the future.

SUMMARY
Management of patient on ECMO imposes a multidisciplinary approach and nutritional
therapy is one of the important factors contributing to the recovery of these patients.
Available literature supports EN, which is safe, well tolerated by patients receiving ECMO.
Commencement of EN early, preferably within 24 hours, should be encouraged. Nasogastric
route is the preferred route for administration of nutritional support. Even mode of ECMO does
not have any significant impact upon delivery of EN, although more prospective studies are
required to evaluate the difference. Supplementary or total parenteral nutrition is considered
in those who cannot achieve sufficient calories and proteins via enteral route or cannot
tolerate EN. Various barriers can challenge an intensivist to initiate early nutritional therapy on
ECMO. Vigilant monitoring of nutritional parameters, symptoms of GI intolerance, and timely
intervention should be documented. There are theoretical concerns regarding safety, timing,
and adequacy of calorie feedings and their impact on morbidity and mortality. Until specific
guidelines are available, it seems reasonable to follow the nutritional guidelines for the general
critically ill adult patients. Available multicenter experiences can also be used as a resource
information to guide the nutritional therapy in patients on ECMO.
Underfeeding in ECMO is still common, as quoted in a recent study by MacGowan L et al.
Thus, adequate energy and protein delivery during VV ECMO is possible,5 especially in those
who are critically ill.

REFERENCES
1. Alberda C, Gramlich L, Jones N, et al. The relationship between nutritional intake and clinical
outcomes in critically ill patients: results of an international multicenter observational study.
Intensive Care Med. 2009;35(10):1728-37.
2. Jaksic T, Hull MA, Modi BP, et al.; American Society for Parenteral and Enteral Nutrition (ASPEN)
Board of Directors. ASPEN clinical guidelines: nutrition support of neonates supported with
extracorporeal membrane oxygenation. JPEN J Parenter Enteral Nutr. 2010;34(3):247-53.
3. Extracorporeal Life Support Organization (ELSO). General Guidelines for Cardiopulmonary
Extracorporeal Life Support. Extracorporeal Life Support Organ. United States: Extracorporeal Life
Support Organization (ELSO); 2013. pp. 1-24.
4. Bear DE, Smith E, Barrett NA. Nutrition support in adult patients receiving extracorporeal
membrane oxygenation. Nutr Clin Pract. 2018;33(6):738-46.
392 Section 2  Extracorporeal Membrane Oxygenation

5. MacGowan L, Smith E, Elliott-Hammond C, et al. Adequacy of nutrition support during


extracorporeal membrane oxygenation. Clin Nutr. 2019;38(1):324-31.
6. Reintam Blaser A, Starkopf J, Alhazzani W, et al.; ESICM Working Group on Gastrointestinal
Function. Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines.
Intensive Care Med. 2017;43(3):380-98.
7. Farías MM, Olivos C, Díaz R. Nutritional implications for the patient undergoing extracorporeal
membrane oxygenation. Nutr Hosp. 2015;31(6):2346-51.
8. Scaravilli V, Zanella A, Sangalli F et al. Basic aspects of physiology during ECMO. In: Sangalli F
(Ed). ECMO Extracorporeal Life Support in Adults, 1st edition. Milan: Springer; 2014. pp. 19-36.
9. Yang S, Wu X, Yu W, et al. Early enteral nutrition in critically ill patients with hemodynamic
instability: an evidence-based review and practical advice. Nutr Clin Pract. 2014;29(1):90-6.
10. Ferrie S, Herkes R, Forrest P. Nutrition support during extracorporeal membrane oxygenation
(ECMO) in adults: a retrospective audit of 86 patients. Intensive Care Med. 2013;39(11):
1989-94.
11. Wollersheim T, Frank S, Müller MC, et al. Measuring Energy Expenditure in Extracorporeal Lung
Support Patients (MEEP)-Protocol, feasibility and pilot trial. Clin Nutr. 2018;37(1):301-7.
12. De Waele E, van Zwam K, Mattens S, et al. Measuring resting energy expenditure during
extracorporeal membrane oxygenation: preliminary clinical experience with a proposed theoretical
model. Acta Anaesthesiol Scand. 2015;59(10):1296-302.
13. Ridley EJ, Davies AR, Robins EJ, et al.; Australian and New Zealand Extracorporeal Membrane
Oxygenation Nutrition Therapy. Nutrition therapy in adult patients receiving extracorporeal
membrane oxygenation: a prospective, multicentre, observational study. Crit Care Resusc.
2015;17(3):183-9.
14. Lukas G, Davies AR, Hilton AK, et al. Nutritional support in adult patients receiving extracorporeal
membrane oxygenation. Crit Care Resusc. 2010;12(4):230-4.
15. Kagan I, Singer P. Nutritional imbalances during extracorporeal life support. World Rev Nutr Diet.
2013;105:154-9.
16. Ohbe H, Jo T, Yamana H, et al. Early enteral nutrition for cardiogenic or obstructive shock requiring
venoarterial extracorporeal membrane oxygenation: a nationwide inpatient database study.
Intensive Care Med. 2018;44(8):1258-65.
17. Scott LK, Boudreaux K, Thaljeh F, et al. Early enteral feedings in adults receiving venovenous
extracorporeal membrane oxygenation. JPEN J Parenteral Enter Nutr. 2004;28(5):295-300.
18. Buck ML, Ksenich RA, Wooldridge P. Effect of infusing fat emulsion into extracorporeal membrane
oxygenation circuits. Pharmacotherapy. 1997;17(6):1292-95.
19. Preiser JC, van Zanten AR, Berger MM, et al. Metabolic and nutritional support of critically ill
patients: consensus and controversies. Crit Care. 2015;19:35.
20. McClave SA, Taylor BE, Martindale RG, et al.; Society of Critical Care Medicine; American Society
for Parenteral and Enteral Nutrition. Guidelines for the provision and assessment of nutrition
support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and
American Society for Parenteral and Enteral Nutrition (ASPEN). JPEN J Parenter Enteral Nutr.
2016;40(2):5159-211.
21. Kreymann KG, Berger MM, Deutz NE, et al.; ESPEN (European Society for Parenteral and
Enteral Nutrition). ESPEN Guidelines on Enteral Nutrition: Intensive care. Clin Nutr. 2006;25(2):
210-23.
22. Zusman O, Theilla M, Cohen J, et al. Resting energy expenditure, calorie and protein consumption
in critically ill patients: a retrospective cohort study. Crit Care. 2016;20(1):367.
23. Berger MM, Reintam-Blaser A, Calder PC, et al. Monitoring nutrition in the ICU. Clin Nutr.
2019;38(2):584-93.
CHAPTER 45
Extracorporeal Membrane Oxygenation and
Sepsis in Intensive Care Unit
Subba Reddy K

INTRODUCTION
The need for usage of multiple invasive procedures and therapies in intensive care unit
(ICU) places the patients at very high risk of nosocomial infections. Among various types
of ICU population, extracorporeal membrane oxygenation (ECMO) patients with multiple
intravascular cannulas, endotracheal tube, urinary catheter, and prolonged duration of ECMO
therapy face enormous risk of acquired infections.
Blood stream infections (BSI), ventilator-associated pneumonia (VAP), and catheter-
associated urinary tract infections (CAUTI) have to be thought of in a patient who had ECMO
initiated more than 48 hours and in a patient within 72 hours of ECMO cessation.

INFECTIONS ON EXTRACORPOREAL MEMBRANE OXYGENATION:


INCIDENCE AND ETIOLOGY
Incidence
The infections among various groups are represented as a ratio of overall percentage of
patients with infections to number of infections per 1,000 days of ECMO support (K days). The
infection rate found on the whole among various groups was 15 infections/1,000 ECMO days
and 11.5%.
Reported infections were also highest in the extracorporeal cardiopulmonary resuscitation
(ECPR) group at 23.6/K days. The neonatal age group showed incidence of 7.9% and 9.9/K days
which was lowest. The adult age group had an incidence of 20.6% and 29.7/K days, which was
the highest.
Among the patients on different modalities of support, venovenous double lumen catheter
group has highest incidence of 20.5/K days which was higher than venoarterial, venovenous
with two cannulas and other modes.

Etiology
The duration of ECMO support has been shown to have a direct relation with the risk of infection
as well as with the raised mortality.1 This has been shown in multiple studies done in pediatric,2
394 Section 2  Extracorporeal Membrane Oxygenation

neonatal,3 adult group4,5 and in cardiac patients6 who undergo ECMO support whereas, a small
study failed to show increased mortality in infected neonatal group on ECMO.7
The prevalence of bacterial and fungal infections varies in different age groups of patients
undergoing ECMO. Coagulase-negative staphylococci (CONS) constitute the highest number
among the neonatal group. Pseudomonas, Staphylococcus aureus and Candida albicans were
the common organisms in the pediatric and adult group of patients. The incidence of CONS is
15.9%, Pseudomonas is 10.5%, and Candida species is 12.7%.
There is significantly elevated risk of fungal infections in seriously ill patients on ECMO
who are suspected of having sepsis, and antifungal treatment should be considered in such
situations.

Salient Points
There is an increased odds ratio of death with evidence of infections in a patient undergoing
ECMO. Increasing age of the patient and length of the ECMO beyond 2 weeks are the factors
which directly correlate with raising incidence of infection.

CIRCUIT MANAGEMENT
All the invasive lines and circuit are potential sources of infections and should be taken
equivalent care to a central line for parenteral nutrition.
Disconnecting the ECMO circuit without a specific need should not be done. Sterility of
the closed loop circuit should be preserved with utmost priority. Habitual sampling from the
lines is not a good practice and should not be done. All the connections and sampling sites are
preferably handled with needleless ports. To lessen the repeated breakage of circuit sterility,
intermittent infusions are to be avoided and continuous infusions to be preferred.
Chlorhexidine is preferred over betadine and alcohol as a preparatory solution. Strict
sterile protocols with chlorhexidine preparation and needleless ports are to be used in initial
connections and changing of lines in the circuit. Drugs and electrolytes should be given as
intermittent boluses to the patient to avoid repeated breakage in the circuit.
All attempts should be made to isolate the ECMO patients from the other patients with
serious infections and resistant organisms as the patients on extracorporeal support are
vulnerable for contamination of blood.
Standard hand hygiene protocols and ICU bundles should be followed by the healthcare
personnel who handle the ECMO circuit.

ANTIBIOTIC PROPHYLAXIS
Multiple invasive lines, possible sources of infection, and prolonged length of ECMO support
complicate the antibiotic usage in the patients.
The practice of prophylactic antibiotic therapy is not encouraged and may give rise to
potential development of resistant bacterial and fungal growth. Some evidence precludes using
prophylactic antibiotics after first 24 hours.2,8 Cardiac group of patients who has undergone
transthoracic cannulation through open thorax are a special group where prophylactic
Chapter 45  Extracorporeal Membrane Oxygenation and Sepsis in Intensive Care Unit 395
antibiotics might be considered as they are at high risk of infections like mediastinitis.2,6,7
For the surgical prophylaxis of cannulation procedure, standard antibiotic principles should
be followed. A single dose of antibiotic or a 24-hour coverage at the maximum should be
acceptable.
In all the vulnerable groups like patients with open chest on multiple antibiotics and
significantly immunocompromised patients, there should be a low threshold for prophylactic
antifungals as they are at high-risk fungal infections.

PREVENTION OF SYSTEMIC INFECTIONS


All the endeavors should be made to prevent nosocomial infections in a patient on ECMO
support. Strict protocolized care of the patient and circuit play a huge role. Sensitization of all
the ICU personnel about the need for infection control measures is essential.
Standard bundles like VAP bundles comprising head end elevation, oral hygiene, acid
reflux prophylaxis should be religiously followed to prevent VAP.
Wherever they are indicated, pulmonary toilet, bronchoscopy, and suctioning have to be
considered.
In the adult patients who are going to require ECMO support for prolonged duration, early
tracheostomy needs to be considered. Tracheostomy helps to decrease the need for sedation
in the patients, improves pulmonary clearance. It also allows the patient to be more awake and
more comfortable. Generation of cough and airway clearance is improved.
Whenever it is appropriate, strict protocols for decontamination oral and gastrointestinal
(GI) tract should be followed.

Nutrition
Early initiation of enteral nutrition is useful in maintaining gut mucosa, preventing
translocation of bacteria, and also lessens the risk of infection in patients on ECMO by avoiding
hyperalimentation. In situations where enteral nutrition is difficult and parenteral nutrition is
needed, it should be preferably given through a dedicated sterile venous access rather than
through the access sites in ECMO circuit because high risk of infection secondary to glucose
concentration. In a situation where the enteral feeding cannot be given and parenteral nutrition
can only be administered through a limited central line, it is recommended that a dedicated
access should be used. It should be managed with strict aseptic measures and should not be
mixed with other infusions.

Invasive Lines and Catheters


Any line, access or device without a specific need should be removed as they increase the
risk of infections on ECMO support. Blood products and medications in intermittent boluses
should be given through peripheral lines whenever available and access sites in the circuit
should be spared.
The removal of longstanding invasive lines, which are not necessary should be done and
the ongoing anticoagulation is not a contraindication for it. The infective risk, and associated
morbidity and mortality are far greater than the bleeding risk from meticulously removed
396 Section 2  Extracorporeal Membrane Oxygenation

venous access. Due to infective and bleeding risks involved, insertion of long-term tunneled
catheters for venous access while on ECMO support is not encouraged.
Any unnecessary long-term lines should be promptly removed, if there is a suspicion of
contamination.

DIAGNOSIS OF INFECTIONS ON EXTRACORPOREAL


MEMBRANE OXYGENATION
In the patients who are on ECMO support, clinical and laboratory diagnosis of infection can
be very difficult. Diagnosing sepsis in a patient on extracorporeal circulation is complicated as
many usual clinical and laboratory markers of sepsis are lost.
The Centers for Disease Control and Prevention criteria for diagnosis of site-specific
infections can be utilized.

Clinical Features
Febrile response in the patient is not easily mounted as the temperature is maintained by
extracorporeal circulation in ECMO. Clinically, the systemic inflammatory response generated
due to the contact of blood with circuit’s foreign surface simulates the sepsis and confuses the
picture.
The symptoms and signs of sepsis should be explored and treated meticulously in an
ECMO patient who could mount an even temperature spike as small as 101°F or more as they
are possibly generating a powerful inflammatory response.

Laboratory Diagnosis
The reliability of leukocytosis and leukopenia is poor at best, particularly in the early ECMO
course where white blood cells (WBCs) are known to be activated by the foreign surfaces
and possibly attach to these sites, especially the membrane of oxygenator which varies
with patient’s response. Total leukocyte count may drop steeply either in the earlier or later
part of the patient’s course. This happens because of the consumption of products by aging
oxygenator. The early elevation in leukocyte count might be cause of response to the circuit
and demargination of white cell pool. Interpretation of any increase or decrease in the WBC
count is difficult without supporting findings. Moderate alterations in leukocyte count should
not be overinterpreted.9
Any acute rise in the WBC count, especially with a significant rise in band cells in an
otherwise stable patient who has been supported for many days on ECMO gives rise to
suspicion of infection.
A very common occurrence is thrombocytopenia because of thrombocyte activation by
surface of the circuit and adherence of the platelets to it. Heparin-induced thrombocytopenia
should not be overdiagnosed.

Imaging
Chest imaging with X-ray is difficult to interpret in the patients on ECMO support, specifically
to diagnose VAP. This is due to frequent opacification due to rest settings on ventilator and
Chapter 45  Extracorporeal Membrane Oxygenation and Sepsis in Intensive Care Unit 397
inflammatory changes seen on ECMO. With expected difficulties of chest X-ray interpretation,
greater importance should be given to the usage of secretions aspirated from airway in
diagnosis of infections.

Surveillance Cultures
Role of daily cultures from 10th day9 and daily tracheal cultures from day 5 of support10 were
studied. Surveillance cultures of sputum and urine, and routine cultures of the blood do not
have strong evidence and are not recommended.

Source Identification
All efforts should be made to diagnose the source of sepsis including diagnostic tests like
bronchoscopy and CT scan as it has been shown that morbidity and mortality due to
undiagnosed sepsis is much higher when compared to the risks involved in well-managed
transport and invasive procedures.

Role of Biomarkers in Diagnosis


Conventional markers like C-reactive protein (CRP) and total leukocyte count could be altered
in patients undergoing ECMO due to multiple reasons. Even procalcitonin production and
release can be incited by multiple noninfective conditions prevalent in patients undergoing
ECMO. Combination of procalcitonin and CRP assay have been used in some studies to have
better sensitivity in detection of infections on ECMO, especially on venoarterial (VA) ECMO.10,11

Difficulties in Diagnosis of Infections on Extracorporeal Membrane Oxygenation


■ Difficulties in standardizing criteria for diagnosing ECMO-related infections.
■ Difficulties in differentiating contamination from real infection.
■ Difficulties in differentiating infections developing post ECMO from those present before
initiation ECMO.

TREATMENT OF INFECTIONS ON EXTRACORPOREAL


MEMBRANE OXYGENATION
Specific guidelines for antibiotic therapy are not there for patients on ECMO support. Use of
prophylactic antibiotics is not encouraged.
Standard principles of antibiotic therapy same as that of other ICU patients should be
applied to treat infections in patients on ECMO. When selecting the required dosage and
frequency of the drugs, volume of distribution should be taken into account. The possibility of
drug sequestration within the membrane, especially lipophilic drugs need to be considered.12-14
Presently standard doses and duration of antibiotics are recommended as the silicone
oxygenators are being discontinued and polymethylpentene oxygenators are being used.
If the antibiotics were started empirically either prophylactically or suspecting an infection
before starting ECMO, they should be continued until the cultures sent before ECMO initiation
return negative and subsequently should be deescalated.
398 Section 2  Extracorporeal Membrane Oxygenation

Usual group of organisms grown in the blood are S. aureus, Pseudomonas, CONS, and C.
albicans. These organisms should be kept in the mind when the choice of empiric antibiotic
therapy is made. As the fungal infections are associated with very high mortality, additional
deliberation should be given to antifungal therapy.
Gram-negative bacilli were responsible for 78% of the nosocomial infections.
Occult abscesses should be investigated. Deliberation in changing all of the ECMO circuit
with possible colonization should be done in ongoing sepsis. Clinical evidence of sepsis or
repeatedly positive blood cultures should guide culture-based antibiotic therapy.

PREPRIMED CIRCUITS
Preprimed circuits are used for rapid initiation of ECMO in emergency situations. Multiple
concerns were raised in the past regarding risk of infections in these preprimed circuits.
It has now been established that it is reasonably safe to maintain circuits free of infections
up to a month and probably beyond a month, if standard strict sterile procedures are followed
in building and priming the circuit.
Also, electrolyte-based solution should be preferred to glucose-based solution or albumin
as a prime.

IMPACT ON PROGNOSIS
Patients on ECMO who develop infections have huge burden of mortality up to 56–68%.
Neonatal group is the most vulnerable group with very high odds ratio of 2.5–2.8 for
mortality.
Acquired infections on ECMO lengthen the duration of ECMO and ICU length of stay. (p <
0.001). On the other hand, significant acquired infections (p < 0.003) are observed in patients
who are on ECMO for more than 10 days.

SUMMARY
In summary, ECMO patients are at increased risk of nosocomial infection when compared
with other patients in the surgical ICU setting.
These patients also lack many of the clinical signs and symptoms associated with
nosocomial infections, thus making the diagnosis difficult; standard definitions for infections
may not apply.
The only independent factor associated with nosocomial infection was prolonged ECMO
use (more than 10 days). Antimicrobial prophylaxis with glycopeptides or antipseudomonal
agents did not correlate with lower rates of nosocomial infection.
The best policy to prevent nosocomial infection in these patients is to correct the underlying
disease process leading to ECMO use and then remove ECMO support as soon as possible.
More studies are needed to enhance the diagnosis of infections, better define risk factors for
infection, and outline prevention strategies for this group of patients.
Chapter 45  Extracorporeal Membrane Oxygenation and Sepsis in Intensive Care Unit 399

REFERENCES
1. Bizzarro MJ, Conrad SA, Kaufman DA, et al.; Extracorporeal Life Support Organization Task Force
on Infections, Extracorporeal Membrane Oxygenation. Infections acquired during extracorporeal
membrane oxygenation in neonates, children, and adults. Pediatr Crit Care Med. 2011;12(3):
277-81.
2. Brown KL, Ridout DA, Shaw M, et al. Healthcare-associated infection in pediatric patients on
extracorporeal life support: the role of multidisciplinary surveillance. Pediatr Crit Care Med.
2006;7(6):546-50.
3. Meyer DM, Jessen ME, Eberhart RC. Neonatal extracorporeal membrane oxygenation complicated
by sepsis. Extracorporeal Life Support Organization. Ann Thorac Surg. 1995;59(4):975-80.
4. Sun HY, Ko WJ, Tsia PR, et al. Infections occurring during extracorporeal membrane oxygenation
use in adult patients. J Thorac Cardiovasc Surg. 2010;140(5):1125-32.e2.
5. Douglass BH, Keenan AL, Purohit DM. Bacterial and fungal infection in neonates undergoing
venoarterial extracorporeal membrane oxygenation: an analysis of the registry data of the
extracorporeal life support organization. Artif Organs. 1996;20(3):202-8.
6. O’Neill JM, Schutze GE, Heulitt MJ, et al. Nosocomial infections during extracorporeal membrane
oxygenation. Intensive Care Med. 2001;27(8):1247-53.
7. Coffin SE, Bell LM, Manning M, et al. Nosocomial infections in neonates receiving extracorporeal
membrane oxygenation. Infect Control Hosp Epidemiol. 1997;18(2):93-6.
8. Kaczala GW, Paulus SC, Al-Dajani N, et al. Bloodstream infection in pediatric ECLS: usefulness
of daily blood culture monitoring and predictive value of biologic markers. The British Columbia
experience. Pediatr Surg Int. 2009;25(2):169-73.
9. Steiner CK, Stewart DL, Bond SJ, et al. Predictors of acquiring a nosocomial bloodstream infection
on extracorporeal membrane oxygenation. J Pediatr Surg. 2001;36(3):487-92.
10. Elerian LF, Sparks JW, Meyer TA, et al. Usefullness of surveillance cultures in neonatal extracorporeal
membrane oxygenation. ASAIO J. 2001;47(3):220-3.
11. Pieri M, Greco T, De Bonis M, et al. Diagnosis of infection in patients undergoing extracorporeal
membrane oxygenation: A case-control study. J Thorac Cardiovasc Surg. 2012;143(6):1411-6.
12. Ahsman MJ, Wildschut ED, Tibboel D, et al. Pharmacokinetics of cefotaxime and desacetylcefotaxime
in infants during extracorporeal membrane oxygenation. Antimicrob Agents Chemother.
2010;54(5):1734-41.
13. Wildschut ED, Ahsman MJ, Allegaert K, et al. Determinants of drug absorption in different ECMO
circuits. Intensive Care Med. 2010;36(12):2109-16.
14. Dagan O, Klein J, Gruenwald C, et al. Preliminary studies of the effects of extracorporeal membrane
oxygenation on the disposition of common pediatric drugs. Ther Drug Monit. 1993;15(4):263-6.
CHAPTER 46
Extracorporeal Membrane Oxygenator as a
Bridge-to-Heart Transplant
Sunil Karanth

INTRODUCTION
The use of extracorporeal membrane oxygenator (ECMO) as a form of mechanical respiratory
and cardiac support has shown a substantial increase over the last few years. Besides
better understanding of the physiology and experience gained in the usage of ECMO, large
technological improvements in the manufacture of different components like oxygenator,
pump, and cannula have aided the greater use of ECMO both in terms of absolute numbers
and expanded clinical indications.
One of the many controversial expanded indications for the use of ECMO is the increasing
use of this modality of support as a bridge-to-heart transplantation or to ventricular assist
devices (VAD). VAD is used as a bridge therapy for patients waiting for a heart transplant.
However, insertion of VAD always needs a complex surgery, which makes it a less preferred,
clinically unpractical option in a critically ill patient. In the latter group of critically ill patients,
ECMO as a form of cardiovascular support, can be considered as a temporizing measure until
further clinical stability is achieved, enabling the patient to be fit to tolerate a complex surgery
for placement of a VAD (called bridge-to-bridge). Heart transplant is the final solution to heart
failure, not responsive to medical therapy. Consequent to the limited availability of donor
organs causing donor shortages, it becomes imperative to develop and use various forms
of bridging therapies as an interim support1 either as a solo modality, in combination or in
sequence.
The last two decades have offered a large volume of experience in the use of ECMO as
a primary cardiac support, allowing newer indications to be considered. Some of the more
recent indications in adults include:
■ Weaning difficulty from cardiopulmonary bypass
■ Cardiogenic shock from any etiology, especially after an acute myocardial infarction (MI)
■ As a bridge-to-heart transplant
■ In the posttransplant setting for the management of primary graft dysfunction (PGD).
In pediatric cardiac patients due to the absence of any other means of cardiac support,
ECMO has become main form of mechanical support as bridging therapy in those who fail to
wean from cardiopulmonary bypass.
Chapter 46  Extracorporeal Membrane Oxygenator as a Bridge-to-Heart Transplant 401

EXTRACORPOREAL MEMBRANE OXYGENATOR AS A


BRIDGE-TO-HEART TRANSPLANT
Increasing need for heart transplants, compounded by expanded indications for transplant
has resulted in a mismatch between the availability of donor organs and the need for the
same. Consequent to the donor shortage, increasing number of patients now need a form
of bridging therapy in the wait for procuring a donor organ for transplant, especially if there
is hemodynamic instability or clinical deterioration. The incidence of patients needing
bridging therapy has increased substantially from 22% to 50%.2 Despite the increased need
for bridging therapy, overall ECMO constitutes only 1.2% of patients as in the majority
continuous flow left ventricular assist device (LVAD) seems to be the preferred mode of
cardiac bridging therapy.3
Despite the rarity of its usage, ECMO does have a major role in specific subset of patients
who are unsuitable for LVAD. ECMO is the preferred mode of support in patients who are
critically ill with hemodynamic collapse or severe biventricular dysfunction. ECMO can also
be used as an alternative when LVAD is not available or cannot be performed due to existence
of an unfavorable anatomy.3
Unfortunately, the outcomes with the use of ECMO as a bridging therapy for heart transplant
remain at best modest and also highly variable. In a retrospective analysis from the French
National Registry [CRISTAL (Colloids Versus Crystalloids for the Resuscitation of the Critically
Ill)], Jasseron et al.4 found that the 1-year posttransplant survival rate of patients needing
ECMO as a bridging therapy to transplant was 70%, in contrast to the comparison group’s
(patients not needing ECMO prior to transplant) survival, which was around 81%. However,
the overall survival of patients needing ECMO as a bridge versus those patients not needing
ECMO was 52.2% and 70.4%, respectively. This indicates that ECMO as a pretransplant bridge,
does offer a certain amount of mortality benefit, though it is lower than patients not needing
ECMO in the pretransplant setting. Chung et al.5 also found only modest survival in their
cohort of 70 patients, with only 31 patients (44%) being able to be bridged to transplant. This
study also showed that age > 50 years, a Sequential Organ Failure Assessment (SOFA) score
of > 10 and pre-ECMO need for cardiopulmonary resuscitation (CPR) were some of the poor
prognostic factors that may predict unsuccessful bridging.
Multiple studies corroborate the poor outcome with the use of short-term mechanical
support like ECMO, as a bridge-to-transplant. Thus, LVAD seems to be the preferred method of
bridging to heart transplantation. ECMO has been mostly used as a bridge-to-bridge (bridge-
to-LVAD), to facilitate stabilization of the patient to undergo a LVAD implantation wherein the
latter would help in successful bridging to heart transplantation. This modus operandi of double
bridge-to-transplant (bridge-to-LVAD using ECMO and bridge-to-heart transplant using
LVAD) is especially useful in patients who become hemodynamically unstable or critically ill
when waiting for transplant or LVAD procedure. Insertion of LVAD requires a complex surgery,
and thus needs the patient to be relatively stable. So any worsening in the patient’s clinical
state during this period, ECMO is considered for stabilization, so that the patient becomes
fit for an LVAD procedure and later on to be bridged to the definitive intervention of heart
transplantation in a staged manner, if an acceptable clinical stability is acquired.6,7 Besides all
of this, there are few occasions wherein, ECMO is preferentially used prior to heart transplant
402 Section 2  Extracorporeal Membrane Oxygenation

(as they are not suitable for LVAD), especially in patients with congenital heart disease,
severe biventricular dysfunction, left ventricular hypertrophy (LVH), or refractory ventricular
arrhythmias.
Pagani8 and colleagues were the first to describe ECMO as a bridge-to-bridge, where the
extracorporeal circuit was used as a bridge to stabilize patients to be able to undergo LVAD
implant so that they could eventually be considered for a heart transplant when feasible.
Using this double bridge strategy, survival of 30–80% has been described in different case
series over the last few years. Tran9 and colleagues found a survival of 45% with the use of
ECMO as a bridge to different VAD procedures. Maresco6 showed a 1-year survival of 75% in
patients supported on VA ECMO for cardiogenic shock before they were bridged to LVAD,
which was similar to survival of patients who were able to be placed on LVAD directly with
no requirement for ECMO as a bridge. This indicates that in patients who are not fit for a
VAD procedure directly, could be stabilized on ECMO by reducing end-organ damage and
optimizing hemodynamics to ensure a successful transition to VAD. Despite this strategy
of double bridge, only 20–40% eventually receives a heart transplantation with successful
outcomes. In view of this modest success, despite the high cost and complexity involved in
the procedure, the scientific community is divided on the utility of the double bridge strategy
in the United States and Europe. The transplant centers in the US favor the double bridge
with the argument that this strategy improves organ utilization. The transplant community
in Europe are of the contrary view that the cost and complexity of this strategy do not justify
its practice.
In the previous section, we discussed about the dilemma and complexity of ECMO prior to
heart transplant largely in adults. But, in patients who are stable for LVAD (exceptions of specific
clinical situations already described), there is no doubt regarding use of these mechanical
devices as a bridge to cure or transplant. In contrast, with the nonavailability of pediatric
VAD and complex congenital problems limiting the use of VAD, the problems encountered in
children with end-stage heart disease is quite different. Because of these reasons, children form
the largest group of patients receiving pretransplant ECMO for end-stage heart failure with
the prevalence of the need for ECMO in the pretransplant setting being as high as 16%.10 The
need for ECMO in the pediatric patients seems to be an independent risk factor for increased
mortality. These children have a two-fold higher risk of death when waiting for a transplant as
compared to children not needing any form of mechanical support, with a 29% mortality after
1 month of waiting and only a 39% overall likelihood of transplantation.11 However, the use of
non-ECMO mechanical support (when feasible), like VAD even in pediatric patients offered
waiting list survival rates similar to patients not requiring mechanical supports classified
as status 1 in the United Network for Organ Sharing (UNOS).12 From the UNOS data, Davies
et al.,13 in an analysis of 431 patients found that children who did not require mechanical
support or were able to be bridged with VAD to a transplant did better, than those pediatric
patients bridged to a transplant on an ECMO. On the other hand, in children below 10 years of
age any form of mechanical support had uniformly bad outcomes.12,14
Let us discuss some of the clinical significant complications11 to be aware when patients are
placed on venoarterial (VA) ECMO. These include:
Chapter 46  Extracorporeal Membrane Oxygenator as a Bridge-to-Heart Transplant 403
■ Infection:
– Vascular catheter-related
– Nonvascular catheter-related:
• Ventilator-associated pneumonia
• Catheter-associated urinary tract infection.
■ Major hemorrhage:
– Needing ≥ 4 units of packed red cells or leading to hemodynamic instability needing
hemodynamic support or intervention
■ Stroke—ischemic stroke or intracranial hemorrhage
■ New initiation of renal replacement therapy
■ Vascular access site complications
■ Ischemia of limbs
■ Ischemia of other organs:
– Bowel ischemia
– Compartmental syndrome.
In summary, due to the complexity of decision-making on placing a patient with end-stage
heart failure on ECMO, having an algorithmic approach of management will facilitate a suitable
care pathway. Designing a structured approach will need to take into consideration a number
of factors including unique patient characteristics such as age, underlying structural cardiac
abnormalities, acuity of decompensation (if any), certainty of transplantation candidacy, and
the likelihood of myocardial recovery. ECMO may be the best method of providing mechanical
support for young patients with palliated or nonpalliated univentricular heart failure. In other
subset of patients, ECMO appears to provide a suitable method of providing rapid mechanical
support in patients who experience refractory, life-threatening myocardial failure. After
stabilization of hemodynamics and appropriate assessment of end-organ functional status,
most of these patients can be transitioned to a more durable form of mechanical circulatory
support, if myocardial recovery is not eminent.
Extracorporeal membrane oxygenation is the preferred method of support in patients
with a combination of myocardial and respiratory failure. But consideration should be given
to transitioning to more durable support options once ECMO is no longer needed to support
respiratory function. Prospective studies that compare various support modalities in different
patient populations are required before data-based guidelines can be developed.

VENTRICULAR ASSIST DEVICES


Ventricular assist devices are a form of mechanical cardiovascular support devices used as
a life-saving measure in patients with acute or chronic heart failure as a bridge therapy or
destination therapy. In doing so, these mechanical devices help improve tissue perfusion and
reverse or prevent organ failure. The devices are classified as paracorporeal (or extracorporeal)
which are placed outside the patient’s body and intracorporeal, placed in the preperitoneal
position either above (pre-pericardial space) or below the diaphragm. The implantable
pumps have external controllers and power sources. The implantable devices can be used
to support left ventricular function [called left ventricular assist device (LVAD)] or right
404 Section 2  Extracorporeal Membrane Oxygenation

ventricular function [called right ventricular assist device (RVAD)] or both [called biventricular
assist devices (BiVAD)]. The BiVAD comprises two separate devices, the LVAD and RVAD for
maintaining optimal cardiac function.15
The mechanical circulatory support devices are of the following types:
■ Paracorporeal (extracorporeal)
– Left ventricular assist device
– Right ventricular assist device
– Biventricular assist device
Examples of paracorporeal devices are pulsatile VAD, continuous flow centrifugal
centrimag ECMO pump, and rotaflow pump.
■ Percutaneous:
– Left ventricular assist device
– Right ventricular assist device
– Biventricular assist device
Examples for the percutaneous devices include tandem heart, Impella LP 5.0/2.5, and
Impella RP.
■ Intracorporeal:
– Biventricular assist device
– Left ventricular assist device.
• Pulsatile, e.g. Thoratec IVAD and Abiomed BVS 500
• Axial continuous—Heartmate II, Jarvik 2000, Heart assist 5, and Incor
• Centrifugal continuous—HVAD, Evaheart, VentrAssist, and Duraheart 5.
The VADs have evolved over time. Based on their historical evolution, they are classified
into the following types:
■ First-generation devices: These devices produce a pulsatile flow mimicking normal
cardiac function. The energy source to achieve ejection is provided by pusher plates
using pneumatic, hydraulic, or mechanical methods. Despite being physiological, these
devices were fraught with numerous risks, significant morbidity, and a limited life span.
Furthermore, implanting these devices was associated with the need for a complex surgery,
and device exchange procedures were associated with an even greater risk.
■ Second-generation devices: These devices have a continuous and nonpulsatile flow
provided by a rotary pump with axial flow having an internal rotor within the blood pump
suspended by contact bearings. They are built on the bearings design akin to a propeller
in a pipe. The spinning of the rotor and flow generation is by the principle of magnetic
coupling of the rotor magnet with the external rotor, e.g. heart mate.
■ Third-generation devices: These devices are the most recent inclusions into the list of
VADs. They work on the principle of noncontact bearings utilizing centrifugal blood flow,
incorporating a magnetic or hydrodynamic levitation of an internal impeller. The impeller
is a short cylinder with an inlet for fluids and vanes for radial flow. The rotation in impeller
is able to provide blood flow by electromagnetic coupling with the pump motor. The
advantages of the third-generation devices have certain advantages on their predecessors.
These include improved reliability and durability, less anticoagulation, greater blood flow,
and reduced risk of suction events in case of reduced blood flow.
Chapter 46  Extracorporeal Membrane Oxygenator as a Bridge-to-Heart Transplant 405

REFERENCES
1. 2016 ELSO International Summary. Ann Arbor, MI: Extracorporeal Life Support
Organization Registry; 2016. [online] Available from: https://www.elso.org/Registry/Statistics/
InternationalSummary.aspx. [Last accessed October, 2019].
2. Lund LH, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart
and Lung Transplantation: Thirty-second Official Adult Heart Transplantation Report--2015; Focus
Theme: Early Graft Failure. J Heart Lung Transplant. 2015;34(10):1244-54.
3. Kirklin JK, Naftel DC, Pagani FD, et al. Sixth INTERMACS annual report: a 10,000-patient database.
J Heart Lung Transplant. 2014;33(6):555-64.
4. Jasseron C, Lebreton G, Cantrelle C, et al. Impact of heart transplantation on survival in patients
on venoarterial extracorporeal membrane oxygenation at listing in France. Transplantation.
2016;100(9):1979-87.
5. Chung JC, Tsai PR, Chou NK, et al. Extracorporeal membrane oxygenation bridge to adult heart
transplantation. Clin Transplant. 2010;24(3):375-80.
6. Marasco SF, Lo C, Murphy D, et al. Extracorporeal life support bridge to ventricular assist device:
the double bridge strategy. Artif Organs. 2016;40(1):100-6.
7. Shah P, Smith S, Haft JW, et al. Clinical outcomes of advanced heart failure patients with
cardiogenic shock treated with temporary circulatory support before durable LVAD implant.
ASAIO J. 2016;62(1):20-7.
8. Pagani FD, Lynch W, Swaniker F, et al. Extracorporeal life support to left ventricular assist device
bridge to heart transplant: a strategy to optimize survival and resource utilization. Circulation.
1999;100(Suppl 19):II206-10.
9. Tran BG, De La Cruz K, Grant S, et al. Temporary venoarterial extracorporeal membrane oxygenation:
ten-year experience at a cardiac transplant center. J Intensive Care Med. 2018;33(5):288-95.
10. Dipchand AI, Rossano JW, Edwards LB, et al.; International Society for Heart and Lung
Transplantation. The Registry of the International Society for Heart and Lung Transplantation:
Eighteenth Official Pediatric Heart Transplantation Report--2015; Focus Theme: Early Graft Failure.
J Heart Lung Transplant. 2015;34(10):1233-43.
11. Lee SY, Jeon KH, Lee HJ, et al. Complications of venoarterial extracorporeal membrane oxygenation
for refractory cardiogenic shock or cardiac arrest. Int J Artif Organs. 2019:391398819868483.
12. Blume ED, Naftel DC, Bastardi HJ, et al. Outcomes of children bridged to heart transplantation
with ventricular assist devices: a multi-institutional study. Circulation. 2006;113(19):2313-9.
13. Davies RR, Russo MJ, Hong KN, et al. The use of mechanical circulatory support as a bridge to
transplantation in pediatric patients: an analysis of the United Network for Organ Sharing database.
J Thorac Cardiovasc Surg. 2008;135(2):421-7.e1.
14. Almond CS, Thiagarajan RR, Piercey GE, et al. Waiting list mortality among children listed for
heart transplantation in the United States. Circulation. 2009;119(5):717-27.
15. Sen A, Larson J S, Kashani KB, et al. Mechanical circulatory assist devices: a primer for critical
care and emergency physicians. Crit Care. 2016;20(1):153.
CHAPTER 47
ECMO in Pediatric Population:
Is it Different from Adults?
Kamlesh Tailor, Nilesh Bohra, Garima Bhag

INTRODUCTION
Extracorporeal life support (ECLS) has been a part of healthcare system for almost last four
decades. The improved extracorporeal membrane oxygenation (ECMO) technology like
refinement of double lumen venous cannulas for pediatric age group, smaller priming volume
of pumps, better oxygenator’s efficiency, changes in circuit design to overcome flow turbulence,
and hemolysis has led to the use of ECMO in more and more challenging patients.1 This earned
experience and confidence for ECMO management has led to its early and elective use in small
neonates to very sick pediatric patients. ECMO has become essential part of any of the tertiary
care neonatal ICU, pediatric ICU, and congenital cardiac unit even in India.
Patient selection remains a key to successful ECMO outcome.
The goal of ECMO support is to provide decent quality of life and achieve patient survival
with least comorbidity. Targeting physiological goals may alter this.

The Key to Successful ECMO


The Key to successful ECMO
1 Case selection and timely initiation
2 Effective monitoring
3 Team’s ability to react for sudden mechanical or patients event

Cumulative summary of procedure types and outcome for the ELSO Registry as of July
2011 is given in Table 1 and overall survival for children and neonates supported by ECMO
as reported to the International Extracorporeal Life Support Organization (ELSO) 2 is given in
Table 2.
■ Neonatal respiratory ECMO has excellent survival on ECMO and survival to discharge as
compared to pediatric respiratory ECMO, and is even five times higher in numbers too
(Table 3).
Chapter 47  ECMO in Pediatric Population: Is it Different from Adults? 407

Table 1: Cumulative summary of procedure types and outcome for the ELSO Registry as of July 2011.2
Neonatal Total Survived ECLS Survived to discharge
Respiratory 24,770 20,951 85% 18,558 75%
Cardiac 4,375 2,649 61% 1,723 39%
ECPR 694 438 63% 270 39%
Pediatric
Respiratory 5,009 3,251 65% 2,785 56%
Cardiac 5,423 3,468 64% 2,609 48%
ECPR 1,347 720 53% 539 40%
(ECPR: extracorporeal cardiopulmonary resuscitation; ELSO: Extracorporeal Life Support Organization)

Table 2: Overall survival for children and neonates supported by ECMO as reported to the International
Extracorporeal Life Support Organization (ELSO).2
Congenital diaphragmatic hernia 50–70%
Meconium aspiration syndrome 90–97%
Primary pulmonary hypertension 75–85%
Respiratory distress syndrome >70%
Sepsis 50–70%
Viral pneumonia 60–80%
Bacterial pneumonia 60–90%
Aspiration pneumonia 75%
Acute respiratory distress syndrome 50–70%
Non-ARDS respiratory failure 50–80%
(ECMO: extracorporeal membrane oxygenation; ARDS: acute respiratory distress syndrome)

Table 3: Factor affecting mortality with pediatric ECMO for respiratory failure.1
Increased survival Increased death
Young age Age > 10 years
ECMO for asthma ECMO for pertussis/sepsis
ECMO for viral pneumonitis/bronchiolitis ECMO with renal failure/dialysis
ECMO for aspiration pneumonitis Cardiac arrest prior to ECMO
Severe acidosis
Duration of ventilation >14 days
High airway pressure
Immune deficiency or impairment
(ECMO: extracorporeal membrane oxygenation)

HISTORY
The history of ECMO has been specified in Table 4.3
408 Section 2  Extracorporeal Membrane Oxygenation

Table 4: History.3
Year Event
1635–1703 Robert Hooke introduced concept of an oxygenator
1916 Jay Maclean discovered heparin from canine heart muscle
1930s Further development of the concept of the oxygenator by Gibbon and Kirkland
1953 First successful human intracardiac surgery by using CPB machine and artificial oxygenator
1972 First adult survivor on ECMO reported by Hills
1972 “Buying time with artificial lungs” published in the New England Journal of Medicine by Zapol
1975 Dr Robert Bartlett reported the first baby to survive on ECMO after 72-hour support, a baby
Esperanza who suffered with meconium aspiration syndrome and PPHN
1978 Kolobow and Gattinoni described removal of CO2 with the use of ECMO and hence reducing
lung injury associated with ventilation
1989 Founding of the Extracorporeal Life Support Organization (ELSO)
2009 Clinical success with ECMO in pandemic outbreak of H1N1 influenza
(CPB: cardiopulmonary bypass; ECMO: extracorporeal membrane oxygenation; PPHN: persistent pulmonary
hypertension of the newborn)

INDICATIONS FOR ECMO


Respiratory ECMO for Neonates
“Reversible respiratory failure but refractory to maximal medical management”

Oxygen Index = MAP × FiO2 × 100/Postductal PaO2


■ Oxygen index > 40 for more than 4 hours
■ Oxygen index > 20 refractory to maximal medical management >24 hours
■ Acute decompensation (PaO2 < 40) with hypoxic respiratory failure not responding to
intervention
■ Progressive respiratory failure with/without pulmonary hypertension in association with
RV dysfunction4
■ Neonate on nitric oxide with an oxygen index of >25 (with damaged lungs).
Most common indications for respiratory ECMO by age is given in Table 5.5

Contraindications for Neonatal Respiratory ECMO


■ Chromosomal disorder includes trisomy 13 and 18
■ Irreversible and significant brain injury
■ Uncontrolled bleeding
■ Intraventricular hemorrhage (≥Grade III).4

Relative Contraindications
■ Irreversible major organ damage (if not considered for organ transplant)
■ Neonate less than 1.6 kg weight2
■ <34 weeks of gestational age (higher chances of intracranial hemorrhage)
■ Ventilatory support for more than 14 days.4
Chapter 47  ECMO in Pediatric Population: Is it Different from Adults? 409

Table 5: Most common indications for respiratory ECMO by age (Frequency %).5
Neonatal Pediatric
Congenital diaphragmatic hernia (30%) Respiratory failure—non-ARDS (20%)
Meconium aspiration syndrome (25%) Viral pneumonia (20%)
Primary pulmonary hypertension (20%) Bacterial pneumonia (8%)
Sepsis (5%) Acute respiratory distress syndrome (6%)
Respiratory distress syndrome (1.5%) Aspiration pneumonia (1%)
Others (18.5%) Others (45%)
(ARDS: acute respiratory distress syndrome; ECMO: extracorporeal membrane oxygenation)

Indications for Pediatric Venoarterial ECMO


■ Preoperative resuscitation
■ Inability to wean from cardiopulmonary bypass (CPB) after cardiac surgery:
– Due to severe myocardial dysfunction
– Due to severe pulmonary hypertension
– Due to severe hypoxemia
– Refractory arrhythmias
– Correctable residual defect
■ Postcardiotomy
■ Cardiomyopathy, myocarditis, and bridge-to-transplant
■ In-hospital cardiac arrest and cardiopulmonary resuscitation (CPR).

PHYSIOLOGICAL POINTS TO BE REMEMBERED WHEN ON ECMO


■ On venoarterial (VA) ECMO: Unloading the right ventricle on VA ECMO leads to reduction
in pulmonary blood flow, which in turn reduces LV preload [left ventricular end-diastolic
pressure (LVEDP) and left ventricular end-diastolic volume (LVEDV)].
■ However, afterload to left ventricle is increased by the ECMO arterial flow, which leads to
problems in severely impaired left ventricle or lung.
■ If heart is ejecting during ECMO, coronaries receive blood ejected by LV. In case where
native lung function is very poor, coronary supply will get hypoxic blood, which may
prevent/delay LV recovery.
■ When on ECMO, if heart is not ejecting with closed aortic valve, it can lead to LV distension.
And if LVEDP rises above the mean arterial pressure (MAP) produced by ECMO, it can
cause subendocardial ischemia. Also, rise in left atrial pressure (LAP) can cause pulmonary
venous hypertension, edema, and hemorrhage. Hence, LV venting is imperative in this
situation.

ECMO CANNULATION IN PEDIATRIC PATIENTS


■ Extracorporeal membrane oxygenation cannulation in pediatric patients is difficult to
compare with adult ECMO because cannulas in children occupy a greater cross section of
vasculature as compared to adults.
410 Section 2  Extracorporeal Membrane Oxygenation

■ Femoral veins are relatively less developed.


■ Arterial cannulation for infant: Advisable to perform sternotomy with central cannulation
or open cannulation of one of the carotid arteries.
■ Venovenous double lumen catheter for bigger pediatric patient is available (OriGen and
Avalon) and effective as well but require USG or fluoroscopic guidance for initial placement.
■ Insertion of these cannulas can be done percutaneously, which may reduce chances of
infection and bleeding.6

Advantages of Using Neck Cannulation


■ Easy to cannulate via surgical cutdown or under ultrasound-guided Seldinger technique
■ Can be cannulated without causing interruption to chest compression during CPR.

Disadvantage of Using Neck Cannulation


■ May risk of blocking right carotid artery, which may lead to stroke in patient with incomplete
circle of Willis (no clear clinical evidence).7

Advantages of Central Cannulation


■ Can cannulate with bigger cannula and hence provide better flow rates
■ Can decompress left ventricle using LV vent.

Disadvantages of Central Cannulation


■ Require surgical team backup
■ Bleeding
■ Infection as chest will be open
■ More chance of dislodgement if patient is awake and moving
■ Require daily X-ray to see cannula position.

Venous Cannula
■ One should select the largest diameter cannula with the shortest length.
■ If patient’s volume status and position of venous cannula are appropriate, the cannula
resistance will be the limiting factor for full ECMO flow.
■ Cannula size is always based on its outer diameter.
■ For adequate and effective venous drainage, most of the venous cannulas have both end
and side holes.
■ To prevent kinking of cannulas, certain cannulas are enforced with wire, e.g. the
BioMedicus® (Medtronic, Minneapolis MN).

Arterial Cannula
■ Due to smaller vessel size, arterial cannula usually has smaller diameter.
■ This leads to a high pressure drop across the cannula.
■ Hence, major determinants of circuit pressure for VA ECMO are pressure drop across the
cannula and the patient’s mean arterial blood pressure.
Cannula size by patient’s weight is demonstrated in Table 6.6
Chapter 47  ECMO in Pediatric Population: Is it Different from Adults? 411

Table 6: Cannula size by patient’s weight.6


Patient’s size (kg) Arterial cannula (Fr) Venous cannula (Fr)
2 8 8–10
3–6 10 10–12
6–8 12 14
8–16 14 17
16–30 17 19
30–40 17 21
>40 21 25

OXYGENATOR
Oxygenator helps in oxygenating blood and removal of carbon dioxide.

Types
Silicone and Hallow Fiber
Advantages of hallow fiber oxygenator are as follows:
■ Shorter prime time and requires low prime volume
■ Low transmembrane pressure gradient
■ Less clot formation due to surface coating.
Disadvantages:
■ Plasma leakage.
First sign of oxygenator failure can be CO2 retention with maximum sweep gas flow.

PUMPS
Pumps are of two types: Roller pumps and centrifugal pumps. In recent years, centrifugal
pumps are being used over roller pumps (Table 7).

ANTICOAGULATION
■ There may be higher chances of intracranial bleed in pediatric ECMO due to immature
coagulation systems and fragile germinal matrices. And even these are the reasons which
make anticoagulation management difficult.
■ Advantages of heparin-coated tubing for ECMO:
– Reduces the requirement for anticoagulation dose for ECMO initiation, which can be
helpful to reduce bleeding complications.
– It reduces platelet activation, prevents circuit clotting.
■ Initial bolus of unfractionated heparin (UFH) 50–100 units/kg will require at the time of
cannulation depending on preexisting bleeding.
■ Unfractionated heparin infusion connected to patient and started at the rate of 5–20
units/kg/hr, once activated coagulation time (ACT) drops to 300, unless there is excessive
bleeding.
412 Section 2  Extracorporeal Membrane Oxygenation

Table 7: Type of pump and its effect on ECMO physiology and flow mechanics.
Roller pump Centrifugal pump
Totally or partially occlusive Nonocclusive
Flow determinant—stroke volume, RPM Flow determinant: Preload and afterload
Higher chances of mechanical trauma to blood Less chances of mechanical trauma to blood
Hemolysis and activation of immune system—high Less hemolysis
(RPM: rotations per minute)

■ Target ACT on ECMO is 160–200 seconds.


■ Since unfractionated heparin (UFH) is dependent on circulating antithrombin (AT), it is
useful to measure AT levels in patients with high requirement of UFH.
■ Anti-factor Xa assay does not correlate very well with heparin dose in practice.
■ Activated partial thromboplastin time (APTT) levels of 1.5–2 times normal are ideal.
■ If ECMO is used for sepsis, anticoagulation management is more difficult due to liver
dysfunction and existing deranged coagulation profile.8
Monitoring coagulation on ECMO.8
Coagulation test Target on ECMO Advantage Disadvantage
ACT 180–200 Bedside method Insensitive to low heparin doses
Easy to use Different reference range with
Immediate result different devices
aPTT (s) 1.5–2 times than Easy to interpret Time consuming
normal Well known monitoring It is advisable to use ratio to avoid
UFH interlaboratory variation
Hemoglobin (g/dL) >10 Easy and quick Not relevant for coagulation
monitoring
Platelet count >75,000 Easy and quick No proven threshold
Platelet function does not reflect
by its count
Anti-Xa assay (IU/ 0.3–0.7 IU/L Sensitive to unfractionated Take more time
mL) heparin Requires calibration
Free Hb and bilirubin could be
underestimated
TEG/ROTEM Can detect platelet Less sensitivity and specificity for
consumption and delay therapy adjustment
onset of coagulation
Fibrinogen (mg/L) 100–150 Useful as a consumption Time-consuming
marker Increased in other inflammatory
situation also
D-dimer (µg/mL) <0.5 Prognostic value for Time-consuming
oxygenator failure Expensive
Antithrombin (AT) % 80–120% Procoagulation marker Heparin resistance not completely
Heparin resistance (partial) rely on AT
(ECMO: extracorporeal membrane oxygenation; ACT: activated coagulation time; aPTT: activated partial
thromboplastin time; ROTEM: rotational thromboelastometry; TEG: thrombelastography; UFH: unfractionated
heparin)
Chapter 47  ECMO in Pediatric Population: Is it Different from Adults? 413
■ In recent studies to guide heparin regimens about 42% used APTT/ACT, about 11%
ECMO centers used the anti-FXa and about 9% used the thrombelastography (TEG) or a
combination of tests.8-10
■ D-dimers can be useful as a marker for ongoing thrombosis and thrombolysis and hence it
can also guide to determine the urgency to change the oxygenator.
■ In one study, the author used increase in D-dimers value as a very early precursor of oxygen-
ator failure (13 patients study). The same group, in another study suggested to monitor
this parameter when any doubt of oxygenator malfunction. Nevertheless, change of the
oxygenator indicated if the oxygen transfer or removal of carbon dioxide are impeded.11,12

Monitoring child on ECMO—our unit protocol.

Test Monitoring Remark


Arterial blood gas 2nd hourly—on first day To assess patient and ECMO as a whole
4th hourly—from second day
Venous blood gas 4th hourly To assess tissue extraction
ACT-bedside 2 hourly (target 180–200) Titrate heparin infusion
If <160, give bolus 10–20 IU/kg and
repeat after hour
aPTT (s) 4 hourly (target 2 times of Correlate value with ACT and fine tune heparin
normal) infusion
If ACT value consistently coming down and
aPTT>2 times, evaluate further
Hemoglobin (g/dL) Twice a day Sudden drop in Hb—search for site of bleeding
>10 for VA and >12 for aggressively
VV ECMO
Platelet count Twice a day If persistently low W/F HIT and treat
Target >75,000
Total leukocyte count Twice a day Trend is important—W/F infection if persistently
high or very low
Serum electrolyte Twice a day Na, K, Ca, Mg supplement if deficit to avoid
arrhythmias
PT/INR Twice a day In bleeding child with high INR- transfuse FFP,
Target 1.2–1.5 cryoprecipitate
Chest X-ray Once a day R/O collection, cannula position, lung
parenchyma
Echo Once a day Monitor ventricular function, cannula position,
R/O clot or vegetation
Pupils Every 4–6 hourly Size, reaction to light, equality
NIRS Continuous–Frontal Value <50 or reduction by >20% should be
alarming
USG skull Once in two days and when Very useful in small children, can assess bleed in
required brain
Urine output Hourly Volume and color—good marker for kidney
perfusion and adequacy of cardiac output

Contd...
414 Section 2  Extracorporeal Membrane Oxygenation

Contd...

Test Monitoring Remark


Premembrane and 8 hourly To assess function of oxygenator
postmembrane gas
Premembrane and Continuous To assess function of oxygenator
postmembrane pressure Target<30 mm Hg
gradient
(ACT: activated coagulation time; ECMO: extracorporeal membrane oxygenation; NIRS: near-infrared
spectroscopy; USG: ultrasonography)

Table 8: Recommended full flow on ECMO.6


Weight of child ECMO flow (cc/kg/min)
<7 kg 120–200
7–10 kg 100–150
10–20 kg 80–120
20–25 kg 100
>25 kg 80
(ECMO: extracorporeal membrane oxygenation)

Table 9: Factor affecting oxygen exchange during ECMO.


Patient’s factor Machine’s factor
Hemoglobin level ECMO—FiO2
Lung condition (when not on full flow) Total ECMO flow
FiO2—ventilator (when not on full flow) ECMO—preload and afterload
Amount of blood going through native pulmonary Membrane capacity/condition
circulation—LV ejection
Patient’s oxygen demand/tissue O2 extraction Amount of blood going through ECMO oxygenator
(ECMO: extracorporeal membrane oxygenation; LV: left ventricular)

FLOW IN PEDIATRIC ECMO


ECMO Flow is Preload Dependent and Afterload Sensitive
ECMO flow according to the cardiac index (CI):

“Full ECMO flow = 2.4 L/min/m2”


Extracorporeal membrane oxygenation flow according to the weight of the child is given
in Table 8.
Hence on ECMO, child has to be adequately filled with reduced afterload to optimized
cardiac output and adequate tissue perfusion.
Chapter 47  ECMO in Pediatric Population: Is it Different from Adults? 415

Table 10: Factor affecting CO2 exchange during ECMO.


• Sweep flow = Gas flow for ECMO (normally start with 1:2 amount, and titrate according to CO2)
• ECMO membrane condition (CO2 value is very sensitive sign of oxygenator failure, once R/O, other factor
• CO2 gradient
• Patient’s lung condition when not on full flow
(ECMO: extracorporeal membrane oxygenation)

Many units dealing with pediatric ECMO including ours follows cardiac index and flow
description.
Factors affecting oxygen exchange and carbon dioxide exchange on ECMO are shown in
Tables 9 and 10.

STRATEGIES FOR INOTROPES ON PEDIATRIC VA ECMO


■ Aim is to rest lung and heart on VA ECMO
■ Hence, choosing and optimizing inotropes should be prioritized once child stabilized for
initial few hours on ECMO
ECMO flow calculation, for example—child’s BSA = 0.25m2
Cardiac index (L/min/m2) CI × BSA Cardiac output = ECMO flow
3 3 × 0.25 0.75 L/min
2.4 (full flow ) 2.4 × 0.25 0.60 L/min (full flow)
2.2 2.2 × 0.25 0.55 L/min
2.0 2.0 × 0.25 0.50 L/min
1.8 1.8 × 0.25 0.45 L/min
1.6 1.6 × 0.25 0.40 L/min
1.2 (half flow ) 1.2 × 0.25 0.30 L/min (half flow)
1.0 1.0 × 0.25 0.25 L/min
0.5 0.5 × 0.25 0.12 L/min
(BSA: body surface area; ECMO: extracorporeal membrane oxygenation)
Cardiac output (CO) = cardiac index (CI) × BSA
■ Goal should be to reduce systemic vascular resistance (SVR) which will reduce ECMO
afterload leading to improved cardiac output and tissue perfusion.
■ Preferred choice will be inodilator like milrinone (0.5–0.75 µg/kg/min) and/or
levosimendan (0.06–0.12 µg/kg/min).
■ If child still has cold periphery and persistent high lactate value with echo finding of poor
LV function, we like to add injection phenoxybenzamine (0.05–0.1 mg/kg/hr) after starting
milrinone/levosimendan.
■ Injection adrenaline dose should be tapered to minimal or tapered off for initial few days of
VA ECMO with full flow; this will reduce myocardial oxygen demand and help other body
organ to recover. This will reduce tachycardia and incidence of arrhythmia also.
■ Injection adrenaline can be restarted once cardiac function improves and weaning from
ECMO flow.
416 Section 2  Extracorporeal Membrane Oxygenation

LEFT VENTRICLE VENTING DURING PEDIATRIC VA ECMO


■ Prevent the left ventricle distension, pulmonary edema, and subendocardial ischemia.
■ Left ventricle venting depends on the age of the patient, the chest is open/closed, and the
anticipated duration of the ECMO run.
■ Left ventricle venting can be done through atrial septostomy, through superior pulmonary
venous cannula, transseptally, left atrial appendage (LAA) or the LV apex.10
■ It is very useful, especially when we are dealing with post-cardiac surgery child and
presence of biventricular failure.
■ As a unit policy, we put LV vent in all the patients where severe left ventricular dysfunction
leads to ECMO placement and this will help in emptying the LV completely and definitely
helps in early recovery of left ventricles.
■ One needs to be careful of LV vent clotting off especially in neonates when left atrium (LA)
pressures drop with improvement in cardiac function. To maintain patency, the solution
can partially occlude the main venous drainage ECMO cannula, which will allow venous
flow from vent.
■ Left ventricle vent should be removed surgically by opening the chest again if it is closed
(Fig. 1).

VENTILATION STRATEGIES ON ECMO


Ventilation strategies on ECMO is given in Table 11.13

VA ECMO in Single Ventricle Physiology Patients


ECMO and Norwood with Modified Blalock–Taussig Shunt (mBTS)
■ Norwood stage I palliation (Fig. 2A) is performed in presence of hypoplastic left heart
syndrome where arch repair done using native pulmonary valve, trunk, and for pulmonary
blood flow either BT shunt or RV-PA conduit placed.

Fig. 1: Chest X-ray showing child on central VA ECMO with RA, LA, and aortic cannula in position.
(LA: left atrium; RA: right atrium; VA ECMO: venoarterial extracorporeal membrane oxygenation)
Chapter 47  ECMO in Pediatric Population: Is it Different from Adults? 417

Table 11: Ventilation strategies on ECMO .13


Goal Action
Avoid “Alveolar strain” Ultraprotective lung ventilation: TV < 4 mL/kg wt
Avoid “Atelectrauma” Maintain high level PEEP ≥ 10 cm H2O
Limit “ Reabsorption atelectasis” Reduce ventilator FiO2 and maintain adequate PEEP
Avoid overdistension Monitor transpulmonary pressure and low TV ventilation
(ECMO: extracorporeal membrane oxygenation; TV: tidal volume; PEEP: positive end-expiratory pressure)

■ Goal is to maintain Qp:Qs—in presence of BT shunt during ECMO run, there may be
chances of significant pulmonary over-circulation can happened at the cost of systemic
under-perfusion.
■ To maintain adequate systemic flow, one might need to increase ECMO flow (>150 mL/kg/
min).
■ Minimize systemic vascular resistance (SVR) to improve ECMO systemic flow and tissue
perfusion.
■ Either minimize the dose of systemic vasoconstrictors or add inodilator to reduces SVR on
ECMO.
■ Avoid excessive hypothermia.
■ Pulmonary flow reduction can be achieved via surgically clipping mBTS indicated
especially when significant stealing of ECMO flow occurs across BT shunt.

ECMO after Bidirectional Glenn Procedure


■ Bidirectional Glenn (BDG) surgery (Fig. 2B) is performed in single ventricle physiology, where
superior vena cava (SVC) will be attached to pulmonary artery to improve pulmonary blood
flow.
■ Two venous cannulas required—one for SVC and other for inferior vena cava (IVC)
drainage to maintain adequate venous drainage and ECMO flow.
■ Superior vena cava decompression is very important during ECMO to avoid cerebral
venous hypertension.
■ In same way, IVC decompression helps in avoiding systemic venous hypertension.
■ In presence of aorta-pulmonary collaterals (APCs)—higher ECMO flow as indicated to
compensate for stealing of systemic ECMO flow.

ECMO after Fontan Procedure


■ Fontan procedure is a staged palliation performed after BDG surgery, where now IVC
also is attached to pulmonary artery by artificial conduit. This is also called as total
cavopulmonary connection.
■ For ECMO in these cases, SVC and IVC cannulation is required for adequate flow and
decompression of venous system.
418 Section 2  Extracorporeal Membrane Oxygenation

B
Figs. 2A and B: (A) Norwood stage I procedure for hypoplastic left heart syndrome; (B) Bidirectional Glenn
surgery for single ventricle physiology.

Risk Factors for Poor Outcomes when ECMO Support Used in Cavopulmonary
Shunted Patients
■ Poor single ventricle function
■ Inadequate systemic perfusion
■ Systemic venous return—not adequate
■ Chronic systemic venous hypertension in presence of low cardiac output
■ Hypoperfusion to brain.
Chapter 47  ECMO in Pediatric Population: Is it Different from Adults? 419

KEY MESSAGES FOR PEDIATRIC ECMO


■ Early initiation or elective ECMO will provide significantly better outcome in pediatric and
neonatal age group.
■ When ECMO is used as a “Bridge-to-Recovery” all efforts is directed toward aggressive
management to the underlying problem and its treatment. This will reduce overall ECMO
duration and its complications.
■ For pediatric ECMO, it is very important to choose appropriate arterial/venous cannula and
decision for peripheral/central cannulation which will reduce cannulation complications
and will be able to provide optimal ECMO flow.
■ Managing anticoagulation on ECMO many a time is difficult in neonates compared to
older children. Hence, careful monitoring is required for cerebral bleed in these babies.
■ Results for pediatric cardiac ECMO are far better if put electively than after cardiac arrest.
■ Managing pediatric cardiac ECMO in single ventricle physiology is very difficult as SVR/
pulmonary vascular resistance (PVR) balance determines tissue perfusion/hypoxia.
Keeping superflow or high ECMO flow is recommended in single ventricle physiology.
■ Nutritional support and infection prevention policies play a major role in pediatric ECMO
outcome.
■ Team work with multidisciplinary approach will improve overall pediatric ECMO success
rate.

REFERENCES
1. Maslach-Hubbard A, Bratton SL. Extracorporeal membrane oxygenation for pediatric respiratory
failure: history, development and current status. World J Crit Care Med. 2013;2(4):29-39.
2. Annich GM, Lynch WR, MacLaren G. ECMO in Critical Care Book, 4th edition. Ann Arbor (MI):
Extracorporeal Life Support Organization; 2012.
3. Vuylsteke A, Brodie D. ECMO in Adult Patients. UK: Cambridge University Press; 2017. .
4. Extracorporeal Life Support Organization (ELSO). (2017). ELSO Neonatal Respiratory Failure
Supplement to the ELSO General Guidelines. [online]. Available from: https://www.elso.org/
Portals/0/ELSOGuidelinesNeonatalRespiratoryFailurev1_4.pdf. [Last accessed November, 2019].
5. Robinson S, Peek G. The role of ECMO in neonatal and paediatric patients. Pediatr Child Health.
2015;25(5):222-7.
6. Harvey C. Cannulation for neonatal and pediatric extracorporeal membrane oxygenation for
cardiac support. Front Pediatr. 2018;6:17.
7. Kurkluoglu M, Hynes CF, Alfares FA, et al. Choice of peripheral venoarterial extra-corporeal mem-
brane oxygenation cannulation site in patients above 15 kilograms. J Card Surg. 2015;30(5):461-5.
8. Mulder MM, Fawzy I, Lance MD. ECMO and coagulation: a comprehensive review. Neth J Crit
Care. 2018;26(1):6-13.
9. Esper SA, Welsby IJ, Subramaniam K, et al. Adult extracorporeal membrane oxygenation: an
international survey of transfusion and anticoagulation techniques. Vox Sang. 2017;112(5):443-52.
10. Ranucci M, Baryshnikova E, Cotza M, et al.; Group for the Surgical and Clinical Outcome Research
(SCORE). Coagulation monitoring in postcardiotomy ECMO: conventional tests, point-of-care, or
both? Minerva Anestesiol. 2016;82(8):858-66.
11. Dornia C, Philipp A, Bauer S, et al. D-dimers are a predictor of clot volume inside membrane
oxygenators during extracorporeal membrane oxygenation. Artific Organs. 2015;39:782-7.
12. Lubnow M, Philipp A, Dornia C, et al. D-dimers as an early marker for oxygenator exchange in
extracorporeal membrane oxygenation. J Crit Care. 2014;29(3):473.e1-5.
13. Schmidt M, Pellegrino V, Combes A, et al. Mechanical ventilation during extracorporeal membrane
oxygenation. Crit Care. 2014;18(1):203.
CHAPTER 48
Extracorporeal Membrane
Oxygenation MCQs
Sandesh KJ, Yash Javeri, Deo Shankar Patel

1. Murray score quantifies the severity of lung disease on the basis of:
a. PF ratio
b. Positive end-expiratory pressure (PEEP)
c. Age d. Chest radiology
Ans. (c) Age
2. Heparin acts on:
a. Xa b. Va
c. IXa d. IIa
Ans. (b) Va
3. Which of the following statements is true with respect to activated coagulation
time (ACT)?
a. ACT is a whole blood test
b. ACT is the time between the exposure of whole blood to glass and formation of
thrombus
c. Measures the heparin effect
d. ACT test will not vary in their sensitivity to heparin
Ans. (d) ACT test will not vary in their sensitivity to heparin
4. A 48-year-old male patient weighing 108 kg is admitted to ICU with acute hypoxemic
respiratory failure. He has a PF ratio of 70 despite optimal ventilation, sedation,
and paralysis. Patient was put on ECMO therapy 8 hours post intubation. On day 2
of ECMO therapy patient starts spiking with high-grade fever and now has persis-
tently low PaO2. All of the following statements with respect to above situation are
true, except:
a. Inadequate flow
b. High cardiac output
c. Insertion of an additional drainage cannula will not improve PaO2
d. Measures to decrease O2 consumption are useful in current scenario
Ans. (c) Insertion of an additional drainage cannula will not improve PaO2
Chapter 48  Extracorporeal Membrane Oxygenation MCQs 421
5. All of the following statements with respect to oxygenation in VV ECMO are true,
except:
a. Fully O2-saturated blood from the ECMO circuit mixes in the right atrium with
deoxygenated venous return
b. Recirculation refers to oxygenated blood from the return cannula flowing directly
to the drainage cannula of the ECMO circuit
c. Systemic arterial oxygenation is not affected by the degree of pulmonary dysfunction
d. Recirculation fraction increases with increasing ECMO flow
Ans. (c) Systemic arterial oxygenation is not affected by the degree of pulmonary
dysfunction

6. Systemic arterial oxygenation in VV ECMO is determined by:


a. The relative proportions of oxygenated ECMO blood flow and deoxygenated
venous return
b. The rate of fresh gas flow
c. Amount of recirculation in the ECMO circuit
d. Oxygenator efficiency
Ans. (b) The rate of fresh gas flow

7. All of the following statements are true, except:


a. VV ECMO improves arterial oxygenation increasing oxygen content of mixed
venous blood
b. Recirculation accounts for the difference in oxygen content between CvO2 and the
oxygen content of the blood entering the membranous lung
c. The oxygen content of blood is highly dependent on the concentration and
saturation of hemoglobin
d. Ventilation/perfusion matching has no effect on the oxygen transfer through
membranous lung
Ans. (d) Ventilation/perfusion matching has no effect on the oxygen transfer through
membranous lung
8. During VV ECMO, SvmixO2 is mainly determined by all, except:
a. Oxygen saturation of the blood leaving the tissues (SvO2),
b. Ratio between extracorporeal blood flow and cardiac output
c. The fresh gas flow rate
d. The presence of recirculation
Ans. (c) The fresh gas flow rate

9. Which subgroup of patients is at risk of Harlequin syndrome?


a. Severe LV dysfunction with abnormal lungs
b. Preserved LV function with normal lungs
c. Severe LV dysfunction with normal lungs
d. Preserved LV function with abnormal lungs
Ans. (d) Preserved LV function with abnormal lungs
422 Section 2  Extracorporeal Membrane Oxygenation

10. In Harlequin syndrome, all of the following statements are true, except:
a. May be overlooked if the arterial blood sampling catheter is positioned in the
femoral artery
b. May be overlooked if the arterial blood sampling catheter is positioned in the
left arm
c. Converting to Veno-venoarterial ECMO is a potential solution
d. Cerebral oxygenation is normal
Ans. (d) Cerebral oxygenation is normal
11. Indications for ECMO include all, except
a. Cardiopulmonary resuscitation (CPR)
b. Refractory hypoxemia in patient with severe ARDS
c. Bridge to heart or lung transplantation
d. Hemodynamic support in patients with severe aortic regurgitation
Ans. (d) Hemodynamic support in patients with severe aortic regurgitation
12. The most appropriate statements regarding venovenous ECMO (VV ECMO)
include:
a. Two cannulas are always required
b. Thrombocytopenia is frequently seen
c. Patient transportation is contraindicated on VV ECMO
d. Patients must always be sedated
Ans. (b) Thrombocytopenia is frequently seen
13. The most appropriate statements regarding the use of ECMO include all, except
a. VA ECMO provides hemodynamic support and gas exchange
b. In severe hypoxemia, arteriovenous ECMO can be done while VV ECMO is ideal
c. The patient commonly needs anticoagulation
d. Bleeding is frequent and may be associated with a fatal outcome
Ans. (b) In severe hypoxemia, arteriovenous ECMO can be done while VV ECMO is ideal
14. Flow in VV ECMO circuit depends on all, except:
a. The speed of rotation per minute (RPM) of the centrifugal pump
b. Cardiac output
c. Characteristics of the inflow or outflow cannulas
d. Positioning of cannula
Ans. (b) Cardiac output
15. All of the following statements are true, except:
a. Membrane oxygenators are placed proximal to the centrifugal pump
b. Surface of the heat exchanger varies from 0.14 m2 to 0.6 m2
c. Oxygenator is the largest area of contact between the blood and the ECMO circuit
d. Heat exchanger is made of polyurethane, polyester, or stainless steel
Ans. (a) Membrane oxygenators are placed proximal to the centrifugal pump
Chapter 48  Extracorporeal Membrane Oxygenation MCQs 423
16. Criteria for weaning trial are all, except:
a. Mean arterial pressure >70 mm Hg b. Inotropic score less than 25
c. SpO2 > 95% d. Improving 2D echo with EF > 25–30%
Ans. (b) Inotropic score less than 25
17. Causes of hemolysis are all, except:
a. Thrombus in circuit components b. Small size cannula
c. High inlet pressures d. Low flow
Ans. (d) Low flow
18. Respiratory criteria for weaning, include one of the following:
a. Compliance > 0.5 mL/kg b. PaO2 < 65 mm Hg
c. PH < 7.40 d. PaCO2 > 50 mm Hg
Ans. (a) Compliance > 0.5 mL/kg
19. All of the following suggest weaning failure ECMO, except:
a. Hypoxia b. Hypercapnia
c. Increasing filling pressures d. Increasing cardiac output
Ans. (d) Increasing cardiac output
20. Oxygenation in VV ECMO is dependent upon:
a. Sweep gas flow rate
b. Diffusion gradient across the membrane
c. Cardiac output
d. Compliance and resistance characteristics of native lung
Ans. (b) Diffusion gradient across the membrane
21. Volume of distribution is increased due to all of the following, except:
a. Hemodilution b. Circuit adsorption
c. Organ failure d. Systemic inflammation
Ans. (c) Organ failure
22. Causes of worsening recirculation are all, except:
a. Too high flows b. Suboptimal cannula position
c. Low cardiac output d. High intravascular volume
Ans. (d) High intravascular volume
23. All of the following are true regarding ventilator support for patients on ECMO
except:
a. Main goal of ECMO is to support gas exchanges while minimizing the risk of VILI
b. ECMO is an extremely efficient tool for CO2 removal
c. Lung rest has no role in minimizing the risk of barotraumas
d. Extracorporeal Life Support Organization (ELSO) recommend a Pplat limit of
≤25 cmH2O
Ans. (c) Lung rest has no role in minimizing the risk of barotraumas
424 Section 2  Extracorporeal Membrane Oxygenation

24. Which of the following statements regarding VV ECMO cannula is true?


a. Venous(inflow) cannulas are longer than the arterial(outflow) cannulas
b. Outflow cannulas have larger diameter than inflow cannulas
c. Inflow cannulas have multiple perforations compared to outflow cannula to
facilitate flow
d. Recirculation percentage is decreased by positioning the tips of cannulas closer to
each other
Ans. (a) Venous(inflow) cannulas are longer than the arterial(outflow) cannulas
25. All of the following statements regarding the ECMO circuit are false, except:
a. VA ECMO ensures adequate oxygenation and also decreases cardiac work
b. Aortic cannulation is always done in patients on VA ECMO
c. Adequate systemic oxygenation is guaranteed in VV ECMO when the oxygenator
is working appropriately
d. AV ECMO also needs a pump similar to VA ECMO
Ans. (a) VA ECMO ensures adequate oxygenation and also decreases cardiac work

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