HD
HD
HD
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
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
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
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
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!!
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.
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.
6. Indications for Renal Replacement Therapy in ICU: Renal and Nonrenal ....................... 36
Nita George, Vilesh Valsalan Kalthoonical
14. Switch Over from or Termination of Continuous Renal Replacement Therapy ................ 104
Ajith Kumar AK, Topoti Mukherjee
29. Know the Extracorporeal Membrane Oxygenation Machine: Circuit and Hardware........... 238
Vinod Kumar Singh
32. Heparin and Alternatives for Anticoagulation in Extracorporeal Membrane Oxygenation ... 275
Muralidhar Kanchi
35. Sedation and Pain Management on Extracorporeal Membrane Oxygenation .................. 301
Babu Abraham, Ajay Padmanaban
45. Extracorporeal Membrane Oxygenation and Sepsis in Intensive Care Unit .................... 393
Subba Reddy K
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
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.).
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.
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.
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.
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.
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.
REFERENCES
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.
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.
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).
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
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.
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.
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
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
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.
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.
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
■ 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).
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.
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
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.
■ 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
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
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
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
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.
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.
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).
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
(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
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).
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.
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. 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.
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)
■ 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.
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
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
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.
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 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.
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.
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.
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.
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.
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
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
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.
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.
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.
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.
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 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
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.
■ 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
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.
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.
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.
■ 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.
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
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
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
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
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.
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.
2016;68(4):599-608.
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)].
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
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.
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
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
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.
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.
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
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
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.
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 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...
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).
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)
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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
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)
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.
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
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.
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.
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.
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.
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.
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
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
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
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.
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
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)
■ 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.
2. HPHD
3. PFD
4. CPFA
■ 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.
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)
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)
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
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.
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
Timing of Therapy
Organ behavior and organ failure is a time function. ECT helps support failing organs and
helps strategize regeneration.
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.
■ 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
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.
REFERENCES
1. Singer M, Deutschman CS, Seymour CW, et al. The third International consensus definitions for
sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):801-10.
2. Ronco C, Tetta C, Mariano F, et al. Interpreting the mechanisms of continuous renal
replacement therapy in sepsis: The peak concentration hypothesis. Artificial organs. 2003;27(9):
792-801.
3. Vincent JL, Abraham E, Annane D, et al. Reducing mortality in sepsis: new directions. Crit Care.
2002;6(Suppl 3):S1-18.
4. Lei MG, Gao JJ, Morrison DC, et al. Pathogenesis of sepsis: current concepts and emerging
therapies. Mo Med. 2003;100(5):524-9.
5. Ronco C, Bonello M, Bordoni V, et al. Extracorporeal therapies in non-renal disease: treatment of
sepsis and the peak concentration hypothesis. Blood Purif. 2004;22(1):164-74.
6. Esteban E, Ferrer R, Alsina L, et al. Immunomodulation in sepsis: the role of endotoxin removal
by polymyxin B-immobilized cartridge. Mediators Inflamm. 2013;2013:507539.
7. Opal SM, Scannon PJ, Vincent JL, et al. Relationship between plasma levels of lipopolysaccharide
(LPS) and LPS-binding protein in patients with severe sepsis and septic shock. J Infect Dis.
1999;180(5):1584-9.
8. Rajani M, Yash J, Wattal C, et al. Sepsis-who cares? Int J Pul Inf Diseases. 2017;1(1):1-4.
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9. Extracorporeal Therapies for Sepsis: Current Status, Critical Care Update 2018 (ISCCM). [online].
Available from: https://isccm.org/NewsLetterFiles/1634179260_CCC_January_February_2017_for.
pdf. [Last accessed October, 2019].
10. Rajani M, Javeri Y, Sangwan KS. Sepsis and antimicrobial therapy in trauma patients. International
Journal of Current Advanced Research. 2016;5(Issue 5):915-21.
11. Payen D. Haemoperfusion with polymyxin B membrane: recent results for an old debate! Anaesth
Crit Care Pain Med. 2019;38(1):3-4.
12. Klein DJ, Foster D, Walker PM, et al. Polymyxin B hemoperfusion in endotoxemic septic shock
patients without extreme endotoxemia: a post hoc analysis of the EUPHRATES trial. Intensive Care
Med. 2018;44(12):2205-12.
13. Chang T, Tu YK, Lee CT, et al. Effects of polymyxin B hemoperfusion on mortality in patients
with severe sepsis and septic shock: a systemic review, meta-analysis update, and disease severity
subgroup meta-analysis. Crit Care Med. 2017;45(8):e858-64.
14. Ala-Kokko TI, Laurila J, Koskenkari J. A new endotoxin adsorber in septic shock: observational
case series. Blood Purif. 2011;32(4):303-9.
15. Yaroustovsky M, Abramyan M, Popok Z, et al. Preliminary report regarding the use of selective
sorbents in complex cardiac surgery patients with extensive sepsis and prolonged intensive care
stay. Blood Purif. 2009;28(3):227-33.
16. Adamik B, Zielinski S, Smiechowicz J, et al. Endotoxin elimination in patients with septic shock:
an observation study. Arch Immunol Ther Exp (Warsz). 2015;63(6):475-83.
17. Lipcsey M, Tenhunen J, Sjölin J, et al. Abdominal Septic Shock-Endotoxin Adsorption Treatment
(ASSET)-endotoxin removal in abdominal and urogenital septic shock with the Alteco® LPS
Adsorber: Study protocol for a double blinded, randomized placebo-controlled trial. Trials.
2016;17(1):587.
18. Kellum JA, Johnson JP, Kramer D, et al. Diffusive vs. convective therapy: effects on mediators of
inflammation in patient with severe systemic inflammatory response syndrome. Crit Care Med.
1998;26(12):1995-2000.
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.
21. Tapia P, Chinchón E, Morales D, et al. Effectiveness of short-term 6-hour high-volume
hemofiltration during refractory severe septic shock. J Trauma Acute Care Surg. 2012;72(5):
1228-38.
22. 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.
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
controlled trial. Intensive Care Med. 2013;39(9):1535-46.
24. Borthwick EM, Hill CJ, Rabindranath KS, et al. High-volume haemofiltration for sepsis in adults.
Cochrane Database Syst Rev. 2017;1:CD008075.
25. Clark E, Molnar AO, Joannes-Boyau O, et al. High-volume hemofiltration for septic acute kidney
injury: a systematic review and meta-analysis. Crit Care. 2014;18(1):R7.
26. Livigni S, Bertolini G, Rossi C, et al. Efficacy of coupled plasma filtration adsorption (CPFA)
in patients with septic shock: a multicenter randomised controlled clinical trial. BMJ Open.
2014;4(1):e003536.
27. Gruda MC, Ruggeberg KG, O’Sullivan P, et al. Broad adsorption of sepsis-related PAMP and DAMP
molecules, mycotoxins, and cytokines from whole blood using CytoSorb® sorbent porous polymer
beads. PLoS One. 2018;13(1):e0191676.
Chapter 22 Extracorporeal Therapies in Sepsis 179
28. Malard B, Lambert C, Kellum JA. In vitro comparison of the adsorption of inflammatory mediators
by blood purification devices. Intensive Care Med Exp. 2018;6(1):12.
29. Poli EC, Rimmelé T, Schneider AG. Hemoadsorption with CytoSorb®. Intensive Care Med.
2019;45(2):236-9.
30. Houschyar KS, Pyles MN, Rein S, et al. Continuous hemoadsorption with a cytokine adsorber
during sepsis-a review of the literature. Int J Artif Organs. 2017;40(5):205-11.
31. Kogelmann K, Jarczak D, Scheller M, et al. Hemoadsorption by CytoSorb in septic patients: a case
series. Crit Care. 2017;21(1):74.
32. Schädler D, Pausch C, Heise D, et al. The effect of a novel extracorporeal cytokine hemoadsorption
device on IL-6 elimination in septic patients: a randomized controlled trial. PLoS One.
2017;12(10):e0187015.
33. Kellum JA, Dishart MK. Effect of hemofiltration filter adsorption on circulating IL-6 levels in septic
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
hemodialysis with AN69 membranes. Kidney Int. 1994;45(5):1497-503.
36. McCrea K, Ward R, LaRosa SP. Removal of Carbapenem-Resistant Enterobacteriaceae (CRE) from
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
caused by Staphylococcus aureus and/or methicillin-resistant S. aureus (MRSA). J Microbiol
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).
INVESTIGATIONS
The suggested investigations in pediatric patients with AKI are mentioned in Box 1.
Chapter 23 Renal Replacement Therapy in Children 181
(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.)
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
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.
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).
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
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.
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.
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
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
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.
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.
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
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
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.
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
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)
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
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.
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.
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
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38. Werner NL, Coughlin M, Cooley E, et al. The University of Michigan experience with veno-
venoarterial hybrid mode of extracorporeal membrane oxygenation. ASAIO J. 2016;62(5):578-83.
39. Scott K, Schmidt B. Modes of ECLS. Extracorporeal Life Support for Adults. United States: Humana
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.
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
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. 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
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.
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.
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.
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.
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.
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
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.
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
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
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
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.
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.
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.
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.
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
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.
■ 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).
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
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).
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).
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.
■ 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.
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.
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.
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
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.
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.
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
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%.
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.
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
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.
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.
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).
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.
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.
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
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
■ 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
Advantages
■ Inexpensive
■ Point-of-care test, thus allowing immediate heparin titration.
Chapter 31 Anticoagulation during Extracorporeal Membrane Oxygenation 271
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
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
(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).
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.
Ancrod is not suitable in patients on ECLS and is not commercially available in most
countries including the United States.
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.
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.
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.
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
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
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
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.
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.
REFERENCES
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2. Bartlett RH. Physiology of ECLS. In: Van Meurs KP, Lally KP, Peek G, Zwischenberger (Eds).
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Standards and Guidelines for Perfusion Practice: 2013. J Extra Corpor Technol. 2013;45(3):156-66.
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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.
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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
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
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
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.
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.
REFERENCES
1. Hill JD, O’Brien TG, Murray JJ, et al. Prolonged extracorporeal oxygenation for acute post-traumatic
respiratory failure (shock-lung syndrome). Use of the Bramson membrane lung. N Engl J Med.
1972;286(12):629-34.
2. Kolobow T, Bowman RL. Construction and evaluation of an alveolar membrane artificial heart-
lung. Trans Am Soc Artif Intern Organs. 1963;9:238-43.
3. Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J
Respir Crit Care Med. 1998;157(1):294-323.
4. Zapol WM, Kitz RJ. Buying time with artificial lungs. N Engl J Med. 1972;286(12):657-8.
5. 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.
6. Gattinoni L, Kolobow T, Agostoni A, et al. Clinical application of low frequency positive pressure
ventilation with extracorporeal CO2 removal (LFPPV-ECCO2R) in treatment of adult respiratory
distress syndrome (ARDS). Int J Artif Organs. 1979;2(6):282-3.
7. Serpa Neto A, Schmidt M, Azevedo LC, et al.; ReVA Research Network and the PROVE Network
Investigators. Associations between ventilator settings during extracorporeal membrane oxygenation
for refractory hypoxemia and outcome in patients with acute respiratory distress syndrome: a
pooled individual patient data analysis: Mechanical ventilation during ECMO. Intensive Care Med.
2016;42(11):1672-84.
8. Frenckner B, Palmér P, Lindén V. Extracorporeal respiratory support and minimally invasive
ventilation in severe ARDS. Minerva Anestesiol. 2002;68(5):381-6.
9. Marhong JD, Telesnicki T, Munshi L, et al. Mechanical ventilation during extracorporeal membrane
oxygenation. An international survey. Ann Am Thorac Soc. 2014;11(6):956-61.
Chapter 34 Mechanical Ventilation during Extracorporeal Membrane Oxygenation 299
10. Marhong JD, Munshi L, Detsky M, et al. Mechanical ventilation during extracorporeal life support
(ECLS): a systematic review. Intensive Care Med. 2015;41(6):994-1003.
11. Schmidt M, Pellegrino V, Combes A, et al. Mechanical ventilation during extracorporeal membrane
oxygenation. Crit Care. 2014;18(1):203.
12. Schmidt M, Stewart C, Bailey M, et al. Mechanical ventilation management during extracorporeal
membrane oxygenation for acute respiratory distress syndrome: a retrospective international
multicenter study. Crit Care Med. 2015;43(3):654-64.
13. Pesenti A, Carlesso E, Langer T, et al. Ventilation during extracorporeal support: why and how?
Med Klin Intensivmed Notfmed. 2018;113(Suppl 1):26-30.
14. Brodie D, Bacchetta M. Extracorporeal membrane oxygenation for ARDS in adults. N Engl J Med.
2011;365(20):1905-14.
15. Peek GJ, Mugford M, Tiruvoipati R, et al.; CESAR trial collaboration. Efficacy and economic
assessment of conventional ventilatory support versus extracorporeal membrane oxygenation
for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet.
2009;374(9698):1351-63.
16. 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.
17. Holzgraefe B, Broomé M, Kalzén H, et al. Extracorporeal membrane oxygenation for pandemic
H1N1 2009 respiratory failure. Minerva Anestesiol. 2010;76(12):1043-51.
18. 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.
19. Bonacchi M, Harmelin G, Peris A, et al. A novel strategy to improve systemic oxygenation in
venovenous extracorporeal membrane oxygenation: the “X-configuration”. J Thorac Cardiovasc
Surg. 2011;142(5):1197-204.
20. Bein T, Weber-Carstens S, Goldmann A, et al. Lower tidal volume strategy (≈3 mL/kg) combined
with extracorporeal CO2 removal versus ‘conventional’ protective ventilation (6 mL/kg) in severe
ARDS: The prospective randomized Xtravent-study. Intensive Care Med. 2013;39(5):847-56.
21. Pham T, Combes A, Rozé H, et al. Extracorporeal membrane oxygenation for pandemic influenza
A (H1N1)-induced acute respiratory distress syndrome: a cohort study and propensity-matched
analysis. Am J Respir Crit Care Med. 2013;187(3):276-85.
22. Kipping V, Weber-Carstens S, Lojewski C, et al. Prone position during ECMO is safe and improves
oxygenation. Int J Artif Organs. 2013;36(11):821-32.
23. Combes A, Hajage D, Capellier G, et al.; EOLIA Trial Group, REVA, and ECMONet. Extracorporeal
membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med.
2018;378(21):1965-75.
24. Terragni PP, Del Sorbo L, Mascia L, et al. Tidal volume lower than 6 mL/kg enhances
lung protection: role of extracorporeal carbon dioxide removal. Anesthesiology. 2009;111(4):
826-35.
25. Fanelli V, Ranieri MV, Mancebo J, et al. Feasibility and safety of low-flow extracorporeal carbon
dioxide removal to facilitate ultra-protective ventilation in patients with moderate acute respiratory
distress syndrome. Crit Care. 2016;20:36.
26. Gattinoni L, Tonetti T, Quintel M. How best to set the ventilator on extracorporeal membrane lung
oxygenation. Curr Opin Crit Care. 2017;23(1):66-72.
27. ELSO. (2017). Extracorporeal Life Support Organization (ELSO) Guidelines for Adult Respiratory
Failure. [online]. Available from: https//www.elso.org. [Last accessed October, 2019].
28. Javidfar J, Bacchetta M. Bridge to lung transplantation with extracorporeal membrane oxygenation
support. Curr Opin Organ Transplant. 2012;17(5):496-502.
29. Protti A, Andreis DT, Monti M, et al. Lung stress and strain during mechanical ventilation: any
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
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).
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.
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
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
(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.
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
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.
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
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
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.
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
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
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.
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
1. Mosier JM, Kelsey M, Raz Y, et al. Extracorporeal membrane oxygenation (ECMO) for critically
ill adults in the emergency department: history, current applications, and future directions. Crit
Care. 2015;19:431.
2. Zapol WM, Snider MT, Hill JD, et al. Extracorporeal membrane oxygenation in severe acute
respiratory failure: a randomized prospective study. JAMA. 1979;242(20):2193-6.
3. Holzgraefe B, Broomé M, Kalzén H, et al. Extracorporeal membrane oxygenation for pandemic
H1N1 2009 respiratory failure. Minerva Anestesiol. 2010;76(12):1043-51.
4. 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.
5. Lo Coco V, Lorusso R, Raffa GM, et al. Clinical complications during veno-arterial extracorporeal
membrane oxygenation in post-cardiotomy and non post-cardiotomy shock: still the Achilles’ heel.
J Thorac Dis. 2018;10(12):6993-7004.
6. 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.
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
oxygenation. J Vasc Surg. 2017;65(4):1074-9.
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.
12. Roussel A, Al-Attar N, Alkhoder S, et al. Outcomes of percutaneous femoral cannulation for
venoarterial extracorporeal membrane oxygenation support. Eur Heart J Acute Cardiovasc Care.
2012;1(2):111-4.
13. Moazami N, Moon MR, Lawton JS, et al. Axillary artery cannulation for extracorporeal membrane
oxygenator support in adults: an approach to minimize complications. J Thorac Cardiovasc Surg.
2003;126(6):2097-8.
14. Sabik JF, Lytle BW, McCarthy PM, et al. Axillary artery: an alternative site of arterial cannulation
for patients with extensive aortic and peripheral vascular disease. J Thorac Cardiovasc Surg.
1995;109(5):885-91.
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
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.
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.
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
(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.
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
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
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).
Fig. 3B: Arteriovenous carbon dioxide removal (AVCO2R) or pump-less extra corporeal lung assist.
338 Section 2 Extracorporeal Membrane Oxygenation
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.
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.
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
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.
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.
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.
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.
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.
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
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
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
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
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).
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
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.
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 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
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
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
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 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.
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).
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.
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
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).
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%.
■ 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 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
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.
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.
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.
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.
REFERENCES
1. Hill JD, O’Brien TG, Murray JJ, et al. Prolonged extracorporeal oxygenation for acute post-traumatic
respiratory failure (shock-lung Syndrome). Use of the Bramson membrane lung. N Eng J Med.
1972;286(12):629-34.
2. Lewandowski K. Extracorporeal membrane oxygenation for severe acute respiratory failure. Crit
Care. 2000;4(3):156-68.
3. Schuerer DJ, Kolovos NS, Boyd KV, et al. Extracorporeal membrane oxygenation: current clinical
practice, coding, and reimbursement. Chest. 2008;134(1):179-84.
4. Fleming GM, Sahay R, Zappitelli M, et al. The incidence of acute kidney injury and its effect
on neonatal and pediatric extracorporeal membrane oxygenation outcomes: a multicenter report
from the kidney intervention during extracorporeal membrane oxygenation study group. Pediatr
Crit Care Med. 2016;17(12):1157-69.
Chapter 43 Extracorporeal Membrane Oxygenation and Renal Replacement Therapy 383
5. Medical Advisory Secretariat. Extracorporeal lung support technologies- bridge to recovery and
bridge to lung transplantation in adult patients: an evidence-based analysis. Ont Health Technol
Assess Ser. 2010;10(5):1-47.
6. Bermudez CA, McMullan DM. Extracorporeal life support in preoperative and postoperative heart
transplant management. Ann Transl Med. 2017;5(20):398.
7. Makdisi G, Wang IW. Extra corporeal membrane eoxygenation (ECMO) review of a life saving
technology. J Thorac Dis. 2015;7(7):E166-76.
8. Zwiers AJ, de wildt SN, Hop WC, et al. Acute Kidney injury is a frequent complication in critically
ill neonates receiving extracorporeal membrane oxygenation: a 14-year cohort study. Crit Care.
2013;17(4):R151.
9. Smith AH, Hardison DC, Warden CR, et al. Acute renal failure during extracorporeal support in
the pediatric cardiac patient. ASAIO J. 2009;55(4):412-6.
10. Thongprayoon C, Cheungpasitporn W, Lertjitbanjong P, et al. Incidence and impact of acute
kidney injury in patients receiving Extracorporeal membrane oxygenation: a meta-analysis. J Clin
Med. 2019;8(7)pii: E981.
11. Hamdi T, Palmer BF. Review of extracorporeal membrane oxygenation and dialysis-based liver
support devices for the use of nephrologists. Am J Nephrol. 2017;46(2):139-49.
12. Wolf MJ, Chanani NK, Heard ML, et al. Early renal replacement therapy during pediatric cardiac
extracorporeal support increases mortality. Ann Thorac Surg. 2013;96(3):917-22.
13. Lin CY, Chen YC, Tsai FC, et al. RIFLE classification is predictive of short-term prognosis in
critically ill patients with acute renal failure supported by extracorporeal membrane oxygenation.
Nephrol Dial Transplant. 2006;21(10):2867-73.
14. Chen H, Yu RG, Yin NN, et al. Combination of extracorporeal membrane oxygenation and
continuous renal replacement therapy in critically ill patients: a systematic review. Crit Care.
2014;18(6):675.
15. Sezai A, Shiono M, Orime Y, et al. Renal circulation and cellular metabolism during left ventricular
assisted circulation: comparison study of pulsatile and nonpulsatile assists. Artif Organs.
1997;21(7):830-5.
16. Nemoto M. Experimental evaluation of the influence of complete artificial circulation on renal
circulation and tissue metabolism-comparative study of pulsatile vs nonpulsatile circulation. Ann
Thorac Cardiovasc Surg. 2003;9(6):355-64.
17. Barrett CS, Jaggers JJ, Cook EF, et al. Pediatric ECMO outcomes: comparison of centrifugal versus
roller blood pumps using propensity score matching. ASAIOJ. 2013;59(2):145-51.
18. Villa G, Katz N, Ronco C. Extracorporeal membrane oxygenation and the kidney. Cardiorenal Med.
2015;6(1):50-60.
19. Fleming GM, Askenazi DJ, Bridges BC, et al. A multicenter international survey of renal supportive
therapy during ECMO: the kidney intervention during extra corporeal membrane oxygenation
(KIDMO) group. ASAIO J. 2012;58(4):407-14.
20. Schmidt M, Bailey M, Kelly J, et al. Impact of fluid balance on outcome of adults patients treated
with extracorporeal membrane oxygenation. Intensive Care Med. 2014;40(9):1256-66.
21. Selewski DT, Cornell TT, Blatt NB, et al. Fluid overload and fluid removal in pediatric patients on
extracorporeal membrane oxygenation requiring continuous renal replacement therapy. Crit Care
Med. 2012;40(9):2694-9.
22. Zarbock A, Kellum JA, Schmidt C, et al. Effect of early vs delayed initiation of renal replacement
therapy on mortality in critically ill patients with acute kidney injury: the ELAIN randomized
clinical trial. JAMA. 2016;315(20):2190-9.
23. Yan X, Jia S, Meng X, et al. Acute kidney injury in adult postcardiotomy patients with extracorporeal
membrane oxygenation: evaluation of the RIFLE classification and the Acute Kidney injury
Network criteria. Eur J Cardiothorac Surg. 2010;37(2):334-8.
24. Kilburn DJ, Shekar K, Fraser JF. The complex relationship of extracorporeal membrane oxygenation
and acute kidney injury: causation or association? Biomed Res Int. 2016;2016:1094296.
384 Section 2 Extracorporeal Membrane Oxygenation
25. Santiago MJ, Sánchez A, López-Herce J, et al. The use of continuous renal replacement therapy in
series with extracorporeal membrane oxygenation. Kidney Int. 2009;76:1289-92.
26. Sasser WC, Robert SM, Askenazi DJ, et al. Peritoneal Dialysis: an alternative modality of fluid
removal in neonates requiring extracorporeal membrane oxygenation after cardiac surgery. J Extra
Corpr Technol. 2014;46(2):157-61.
27. Seczyńska B, Królikowski W, Nowak I, et al. Continuous renal replacement therapy during
extracorporeal membrane oxygenation in patients treated in medical intensive care unit: technical
considerations. Ther Apher Dial. 2014;18(6):523-34.
28. Thajudeen B, Daheshpour S, Bijin B. Extracorporeal membrane oxygenation and continuous
0renal replacement therapy. In: Firstenberg MS (Ed). Extracorporeal Membrane Oxygenation.
Rijeka: Intech Open; 2016.
29. Li G, Zhang L, Sun Y, et al. Co-initiation of continuous renal replacement therapy, Peritoneal
dialysis, and extracorporeal membrane oxygenation in neonatal life-threatening hyaline membrane
disease: a case report. Medicine (Baltimore). 2019;98(4):e14194.
30. Blijdorp K, Cransberg K, Wildschut ED, et al. Hemofiltration in newborns treated with Extracorporeal
membrane oxygenation: a case-comparison study. Crit Care. 2009;13:R48.
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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34. deTymowski C, Augustin P, Houissa H, et al. CRRT connected to ECMO: managing high pressures.
ASAIO J. 2017;63(1):48-52.
35. Paek JH, Park S, Lee A, et al. Timing of initiation of sequential continuous renal replacement therapy
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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.
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
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.
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.
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).
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
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.
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.
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.
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.
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.
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
(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 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.
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)
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)
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
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)
Contd...
414 Section 2 Extracorporeal Membrane Oxygenation
Contd...
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.
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
■ 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.
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
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
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