@anesthesia - Books 2017 Yearbook of Anesthesiology - 6

Yearbook of
Anesthesiology-6
EDITORIAL BOARD MEMBERS
VP Kumra MD DA FICA
Past President and Advisor
Indian College of Anaesthesiologists
Ex-Vice President
Indian Society of Anaesthesiologists (National)
Emeritus Consultant and Advisor
Department of Anaesthesiology Pain and Perioperative Medicine
Sir Ganga Ram Hospital
New Delhi, India
[email protected]
B Radhakrishnan MD MPhil FICA

President
Ex-President
Principal
Academy of Medical Sciences
Kannur, Kerala, India
[email protected]
Jayashree Sood MD FFARCS PGDHHM FICA

CEO
Professor and Chairperson
Department of Anaesthesiology Pain and Perioperative Medicine
Honorary Joint Secretary, Board of Management
New Delhi, India
[email protected]
Baljit Singh MD
CEO
Indian College of Anaesthesiologist
Director Professor
GB Pant Institute of Postgraduate Medical Education and Research
New Delhi, India
[email protected]
Yearbook of
Anesthesiology-6
Editors
Raminder Sehgal MD DA FICA
Ex–Director Professor
Maulana Azad Medical College
New Delhi, India
Ex–Senior Consultant
New Delhi, India
[email protected]
Anjan Trikha MD FICA

Professor
Department of Anesthesiology, Pain Medicine and Critical Care
All India Institute of Medical Sciences
New Delhi, India
[email protected]

Whole Constituent of
Indian Society of Anaesthesiologists
(Member of the World Federation of
Societies of Anaesthesiologists)
Foreword
B Radhakrishnan
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Yearbook of Anesthesiology-6
First Edition: 2017
ISBN: 978-93-86261-53-3
Printed at
Contributors
Ajay Kumar MD DM Anju Grewal MD
Associate Consultant Professor
Department of Cardiac Anesthesia Department of Anesthesiology
Medanta–The Medicity Dayanand Medical College and Hospital
Gurgaon, Haryana, India Ludhiana, Punjab, India
[email protected] Editor–in–Chief
Journal of Anaesthesiology Clinical
Ajisha Aravindan MD DNB Pharmacology (JOACP)
Senior Resident [email protected]
Department of Anesthesiology, Critical Care [email protected]
and Pain Medicine
All India Institute of Medical Sciences Aruna Parameswari MD DNB
New Delhi, India Professor
[email protected] Department of Anesthesiology, Critical Care
and Pain Medicine
Akilandeswari Manickam MD Sri Ramachandra University
Professor Chennai, Tamil Nadu, India
Department of Anesthesiology, Critical Care [email protected]
and Pain Medicine
Sri Ramachandra University Ashok K Sethi MD
Chennai, Tamil Nadu, India Director Professor and Head
[email protected] Department of Anesthesiology
University College of Medical Sciences and
Amod Sawardekar MD Guru Teg Bahadur Hospital
Assistant Professor Delhi, India
Department of Pediatric Anesthesiology [email protected]
Ann and Robert H Lurie Children’s Hospital
of Chicago BK Rao MD
Feinberg School of Medicine Senior Consultant
Northwestern University Department of Critical Care and Emergency
Chicago, USA Medicine
[email protected] Sir Ganga Ram Hospital
New Delhi, India
Anil Kumar Jain MD DA DNB [email protected]
Vice Chairperson
Department of Anesthesiology, Pain and Chand Sahai MD
Perioperative Medicine Senior Consultant
Sir Ganga Ram Hospital Department of Anesthesiology, Pain and
New Delhi, India Perioperative Medicine
[email protected] Sir Ganga Ram Hospital
New Delhi, India
Anjali Kochhar MD [email protected]
Associate Professor
Department of Anesthesiology Harshita Singh MD
Hamdard Institute of Medical Sciences and Senior Resident
Research Department of Anesthesia
Jamia Hamdard Tata Memorial Hospital
Delhi, India Mumbai, Maharashtra, India
[email protected] [email protected]
vi Yearbook of Anesthesiology-6
Hema C Nair MD Lakshmanan Parthasarathy MD DA

Senior Consultant Professor
Department of Anesthesia and Critical Care Department of Anesthesiology
Narayana Institute of Cardiac Sciences Tamil Nadu Government Multi Super
Bengaluru, Karnataka, India Speciality Hospital
[email protected] Chennai, Tamil Nadu, India
[email protected]
Jeetinder Makkar MD
Additional Professor LD Mishra MBBS MD PhD FICA
Department of Anesthesia and Intensive Professor and Former Head
Care Department of Anesthesiology
Postgraduate Institute of Medical Education Head
and Research Department of Neuroanesthesia
Chandigarh, India Chairman
[email protected] Coordination Committee for Emergency
Medicine
JV Divatia MD FICCM FCCM Institute of Medical Sciences
Professor and Head Banaras Hindu University
Department of Anesthesia, Critical Care and Varanasi, Uttar Pradesh, India
Pain Management [email protected]
Tata Memorial Hospital
Mumbai, Maharashtra, India Mohd Saif Khan MD DNB
[email protected] Senior Resident
Department of Anesthesia, Critical Care and
Kajal Jain MD Pain Management
Professor Tata Memorial Hospital
Department of Anesthesia and Intensive Mumbai, Maharashtra, India
Care [email protected]
Postgraduate Institute of Medical Education
and Research Naheed Azhar MD DA DNB
Chandigarh, India Professor
[email protected] Department of Anesthesiology
Government Stanley Medical College and
Kamal Fotedar MD DM Hospital
Director Chennai, Tamil Nadu, India
Department of Anesthesiology
Max Super Speciality Hospital Nidhi Bhatia MD
Delhi, India Associate Professor
[email protected] Department of Anesthesia and Intensive
Care
Kirti N Saxena MD Postgraduate Institute of Medical Education
Director Professor and Research
Department of Anesthesiology and Chandigarh, India
Intensive Care [email protected]
Maulana Azad Medical College
New Delhi, India Pradeep Bhatia MD FICCM FICA
[email protected] Professor and Head
Department of Anesthesiology and Critical
Krishna HM MD Care
Professor All India Institute of Medical Sciences
Department of Anesthesiology Jodhpur, Rajashthan, India
Kasturba Medical College Editor–in–Chief
Manipal, Karnataka, India The Indian Anaesthetists’ Forum
Contributors vii
Pramod Kohli MD Sachidanand Jee Bharti MD

Director Professor Assistant Professor
Department of Anesthesiology Department of Onco-Anesthesiology and
Lady Hardinge Medical College Palliative Medicine
New Delhi, India Dr BRA Institute–Rotary Cancer Hospital
[email protected] All India Institute of Medical Sciences
New Delhi, India
Rajeshwari Subramaniam MD [email protected]
Professor
Department of Anesthesiology, Critical Care Santhanam Suresh MD FAAP
and Pain Medicine Anesthesiologist-in-Chief
All India Institute of Medical Sciences Department of Pediatric Anesthesiology
New Delhi, India Ann and Robert H Lurie Children’s Hospital
[email protected] of Chicago
Arthur C King Professor and Chair of
Rakesh Kumar MD DA Anesthesiology
Director Professor Professor
Department of Anesthesiology and Department of Anesthesiology and
Intensive Care Pediatrics
Maulana Azad Medical College Feinberg School of Medicine
Medical Superintendent Northwestern University
Department of Trauma, Emergency and ICU Chicago, USA
Lok Nayak Jai Prakash Narayan Hospital [email protected]
New Delhi, India
[email protected] Sharmila Ahuja MD
Ex–Professor
Renu Sinha MD
Department of Anesthesiology and Critical
Additional Professor
Care
Department of Anesthesiology
University College of Medical Sciences and
Dr RP Centre for Ophthalmic Sciences
Guru Teg Bahadur Hospital
Delhi, India
New Delhi, India
[email protected]
[email protected]
Subrat Dam MD
RP Gehdoo MD
Senior Consultant
Professor
Department of Anesthesia and Critical Care
Department of Anesthesia
Sant Parmanand Hospital
Tata Memorial Hospital
Delhi, India
Mumbai, Maharashtra, India
[email protected]
[email protected]
Sunila Sharma MD
S Loha MBBS MD PDCC (Neuroanesthesia) Director and Head
Assistant Professor Department of Anesthesiology, Pain and
Department of Anesthesiology Perioperative Medicine
Institute of Medical Sciences Fortis Flt. Lt. Rajan Dhall Hospital
Banaras Hindu University New Delhi, India
Varanasi, Uttar Pradesh, India [email protected]
viii Yearbook of Anesthesiology-6
Surender K Malhotra MD FICA Vinod Kalla DA FFARCS

Professor Emeritus Consultant
Department of Anesthesia Department of Anesthesia and Critical Care
Maharishi Markandeshwar University of Sant Parmanand Hospital
Medical Sciences and Research Delhi, India
Mullana, Ambala, Haryana, India [email protected]
[email protected]
Yatin Mehta MD MNAMS FRCA FAMS
Sushma Bhatnagar MD Chairman
Professor and Head Institute of Critical Care and Anesthesiology
Department of Onco-Anesthesiology and Medanta–The Medicity
Palliative Medicine Gurgaon, Haryana, India
Dr BRA Institute–Rotary Cancer Hospital [email protected]
New Delhi, India Zainab Ahmad MD
[email protected] Assistant Professor
Department of Pediatric Trauma and
Vanessa Ng MD Anesthesiology
Clinical Instructor Super Speciality Paediatric Hospital and
Department of Pediatric Anesthesiology Post Graduate Teaching Institute
Ann and Robert H Lurie Children’s Hospital Noida, Uttar Pradesh, India
of Chicago [email protected]
Feinberg School of Medicine
Northwestern University
Chicago, USA
[email protected]
Foreword
The Indian College of Anaesthesiologists (ICA) is proud to present its state-of-the
art publication Yearbook of Anesthesiology-6. This yearbook is the sixth in its series
and, each year, we are achieving increased acceptance of the book in anesthesia’s
academic as well as practice circles. The Indian College of Anaesthesiologists has
a unique distinction of introducing a yearbook for the first time in Indian medical
literature and we are progressing in building our legacy with new introductions
and break-up patterns in publications. The format we have selected is to give a
reasonable understanding on the recent anesthetic literature, then releasing
brief information on nascent conversed anesthetic concepts. This paradigm shift
we are focusing on, with the publication of the yearbook, is being appreciated
by our readers and international peer reviewers. We welcome suggestions from
our readers for any reasonable change of format, if needed, and if no suggestions
are available, we may regard this as our final outlook for presentation to the
international expert committee for indexation.
This edition is carefully panned out to include the recent part of information
and knowledge in anesthesia academics that has come up in the last 5 years, and
aims at a consolidated review of the knowledge. The editors, Raminder Sehgal
and Anjan Trikha, have put in considerable efforts to improve the architecture
of the publication, along with the contributors of each chapter. The ICA wishes
everyone concerned in the promotion of this masterly publication a great success
in his/her career and promises every reader a real thought-provoking package of
medical knowledge.
The ICA congratulates the contributors, editors, and publishers for bringing
out this yearbook. We look forward to varying presentations and improved
knowledge dissemination in future.
B Radhakrishnan MD MPhil FICA

President
Ex-President
Principal
Academy of Medical Sciences
Kannur, Kerala, India
[email protected]
Preface
Yearbook of Anesthesiology-6 is the sixth in its series, brought out by the Indian
College of Anaesthesiologists (ICA). The feedback and the response regarding the
previous editions has been overwhelming that has motivated the editorial team to
bring out the present book. The topics chosen cover all the three specialties that
are associated with anesthesiologists, i.e. anesthesia, pain and intensive care. The
topics chosen are relevant at present times and would be useful for all the clinicians
in the fields mentioned above. Of note would be one of the most trending topics
of enhanced recovery after surgery (ERAS). Most of the hospitals in the world
have adopted the guidelines for enhanced recovery and it is the time that the
same practice be followed in the developing countries. One of the other present
controversies in anesthesia is its effect on immune response in humans and one of
the chapters in this edition highlights the present knowledge on this topic.
Topics related to pharmacology include transdermal drug delivery,
peripheral opioid receptors, opioid-induced hyperalgesia, pharmacokinetics
and pharmacodynamics in obstetrics and present status of dexmedetomidine.
Important areas of anesthesia practice such as nontechnical skills and
medicolegal aspects, have also been covered in detail. Neurological complications
of anesthesia and controversies regarding perioperative use of beta blockers have
also been included in this edition.
The incidence of malignancies in the world is rising and it is but natural that
palliative care would become very important in pain practice. The chapter on
management of palliative pain gives an overview of treatment modalities available
for alleviation of such pain and should immensely benefit those in pain practice.
Regional anesthesia in children has been covered by experts in the field. Pain
issues in children in the perioperative period is another neglected area especially
in the peripheral hospitals and the chapter on assessment of pain in children
and management strategies of pain in this age group gives a summary of all the
options available for improving pain management in children. The latest on the
management of patients with pheochromocytoma, maxillofacial or brain trauma,
anaphylaxis and those presenting for ophthalmic surgery, will be of interest to
students as well as practicing anesthesiologists. Relevance of ICU-scoring systems
and immune modulating diets has been discussed in detail. Lastly, the chapter
on positive end-expiratory pressure (PEEP) and lung recruitment in the intensive
care would be very informative to the postgraduate students and those venturing
into intensive care.
As editors, we narrow down on the topics that we presume would be interesting
for the readers. The Journal Scan covers commentary of experts on topics of
interest published in reputed journals during the year. Feedbacks, suggestions
and criticism regarding the present edition from our readers would be highly
appreciated so that further editions could be improved. We take this opportunity
to express our gratitude to all the contributors to this volume and to the reviewers
for their constructive criticism. Our special thanks go to the dedicated staff of
M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India, for their support.
Raminder Sehgal
Anjan Trikha
Contents
1. Immune Modulating Diet in Critically Ill: Myth or Reality 1
Subrat Dam, Vinod Kalla
Enteral versus Parenteral Nutrition 1
Inflammation and Immune Response 2
Immunonutrition and Pharmaconutrition 2
Role of Individual Immunonutrients 3
2. Medicolegal Issues in Anesthesia 12

Sunila Sharma
Common Causes of Litigations 12
Legal Aspects of Anesthesia 13
Doctor-Patient Relationship 14
Intraoperative Legal Requisites 19
Postoperative Legal Requisites 19
Strategies to Reduce Adverse Patient Outcomes 20
Elements of Medical Negligence 20 • Professional Liability 21
Time Limitation and Court Jurisdiction 22
Outcome of a Court Trial 22
3. Regional Anesthesia in Children 25

Santhanam Suresh, Vanessa Ng, Amod Sawardekar
Upper Extremity Blocks 25 • Truncal Blocks 30
Lower Extremity Blocks 33
4. Pain in Children: Assessment and Management Strategies 41

Sharmila Ahuja
Assessment of Pain in Children 41
Management Strategies for Postoperative Pain in Children 46
Future Perspectives in Pain Management 50
5. Severity of Illness Scoring Systems and Their Clinical Relevance 53

BK Rao
Brief History 53 • Development of Scoring Model 54
Severity of Illness Models 55 • Comparison of Scoring Models 60
Uses of Severity-of-Illness Systems 61
6. Transdermal Drug Delivery 68

Aruna Parameswari, Akilandeswari Manickam
Physiology of Skin and Pathways of Drug Transport 69
Pharmacokinetics of Transdermal Delivery 69
Design and Types of Transdermal Patches 70
Drugs Used as Transdermal Patches 71
Novel Methods of Transdermal Drug Delivery 76
xiv Yearbook of Anesthesiology-6
7. Peripheral Opioid Receptors 82

RP Gehdoo, Harshita Singh
Opioid Receptors 83 • Mechanism of Action 83
Peripheral Opioid Receptors Location 83
Plasticity and Regulation of Opioid Receptor 84
Endogenous Opioid Ligands 85
Migration of Opioid Peptide-Producing Cells to Inflamed Tissue
and Release of Peptides from Immune Cells 86
Modulation of Pain and Inflammation via Peripheral Opioid Receptors 86
Potential for Clinical Applications 87
Novel Peripherally Restricted Opioid Agonists 87
Future Research 88
8. Dexmedetomidine: Perioperative Applications and Limitations 93

Kajal Jain, Jeetinder Makkar
Physiology 93 • Mechanism of Action 93
Clinical Applicatons 94
Dexmedetomidine in Pediatric Anesthesia 98
9. Pheochromocytoma: Current Concepts and Management of

Laparoscopic Excision 103
Rajeshwari Subramaniam, Ajisha Aravindan
Anatomy 103 • Signs and Symptoms 103
Pediatric Pheochromocytoma 105 • Incidentalomas 105
Pathophysiology of Hypertension 105
Genetic Basis of Pheochromocytoma 106 • Diagnosis 106
Preoperative Preparation 108
Surgery for Pheochromocytoma 111
10. Perioperative Anaphylaxis 121

Pradeep Bhatia
Pathophysiology 121 • Risk Factors 121
Perioperative Triggers 122 • Clinical Features 123
Diagnosis 123 • Differential Diagnoses 124
Investigations 124 • Treatment 125
Prevention of Anaphylaxis 126
Future Anesthesia Management 127
11. Effect of Anesthesia on Perioperative Immunity 131

Anju Grewal, Nidhi Bhatia
Components of Immune Response 131
Perianesthesia Stressors 132 • Anesthesia and Immunity 132
Anesthetic Agents and Immunity 133
Anesthetic Techniques and Malignancy 135
Anesthesia and Anaphylaxis 137
Immune Function and Perianesthesia Care: Clinical Implications 137
Contents xv
12. Nontechnical Skills for the Healthcare Provider:

Bringing about Changes in Outlook, Protocols and Policies 141
Hema C Nair
Genesis of Nontechnical Skills in Health Care 142
Classification and Nontechnical Skill Assessment Tools 143
Practical Applications of Nontechnical Skills Assessment 145
Minor Error Classification 146 • Checklists 147
Human Errors Resulting from Technology Mismatch 148
The Epidemic of Preventable Deaths 149
13. Enhanced Recovery After Surgery 152
Ashok K Sethi, Anjali Kochhar, Zainab Ahmad
Components of Enhanced Recovery Protocols 152
Implementation 160
14. Pharmacokinetics in Obstetric Patients 164
Lakshmanan Parthasarathy, Naheed Azhar
Pharmacokinetic Changes 164
Placental Drug Transfer 166
Pharmacokinetics of Common Anesthetic Drugs during Pregnancy 166
Effect of Anesthetic Drugs on Developing Fetus 170
Nitrous Oxide and Safety in Pregnancy 171
15. Opioid-induced Hyperalgesia 174
Pramod Kohli
Historical Considerations 174
Opioid-induced Hyperalgesia and Opioid Tolerance 174
Experimental Evidence for Existence of OIH 175
Clinical Evidence for OIH 175 • Pathogenesis of OIH 176
Sites of OIH Development 178 • Reversing the Effects of OIH 178
Treatment Strategies 179
16. Anesthetic Management of Faciomaxillary Trauma 184
Anil Kumar Jain
Incidence and Etiology of Maxillofacial Trauma 184
Anatomy 185 • Clinical Presentation 185
Airway Management 186 • Basic Airway Management Techniques 187
Factors Affecting Emergency Airway Management in Maxillofacial Trauma 192
Management of Hemorrhage 192 • Other Care 192
Elective or Late Management 192 • Anesthesia Management 193
Postoperative Care 195
17. Critical Care in Head Injured Patients 199
LD Mishra, S Loha
Management of Traumatic Brain Injury in Intensive Care Unit 199
18. Mechanical Ventilation: Tidal Volume, PEEP and Recruitment 210
JV Divatia, Mohd Saif Khan
Ventilator-initiated Lung Injury 210
Tidal Volume in Acute Respiratory Distress Syndrome 213
xvi Yearbook of Anesthesiology-6
Positive End-expiratory Pressure 214 • Concept of Driving Pressure 218

Recruitment Maneuver 218 • Prone Position 220
Low Tidal Volumes and PEEP in Patients with Normal Lungs? 220
19. Palliative and Hospice Care: Need of the Hour to Improve

Quality and Quantity of Life 224
Sushma Bhatnagar, Sachidanand Jee Bharti
Historical Perspective of Palliative Care 224
Scope of Palliative Care 225 • Components of Palliative Care 225
Core Competencies Required in Palliative Care 226
Palliative Care in India 226 • How to Start Palliative Care Services? 227
How to Implement Palliative Care Program in India? 228
20. Update on Anesthesia for Ophthalmic Surgery 231

Renu Sinha
Retinopathy of Prematurity 231
Ultrasound-guided Ophthalmic Blocks 233 • Sub-Tenon’s Block 234
Sedation during Ophthalmic Procedures 235
Antiplatelet and Anticoagulant Therapy and Ophthalmic Anesthesia 236
21. Perioperative Neurological Complications 242

Kirti N Saxena
Postoperative Delirium 242 • Postoperative Cognitive Dysfunction 243
Postoperative Visual Loss 244 • Spinal Cord Ischemia 245
Stroke 246 • Neuroexcitatory Phenomenon 247
Complications of Neuraxial Anesthesia 248
Cranial Nerve Injuries 249 • Peripheral Nerve Injuries 250
22. Perioperative Beta Blockers: To Use or Not to Use 254

Yatin Mehta, Ajay Kumar
Beneficial Effects of Beta Blockers 254
Beta Blockers and Noncardiac Surgery 256
Beta Blockers and Cardiac Surgery 257
Beta Blockers Formulation and Titration 259
23. Biomarkers in Anesthesiology 264

Kamal Fotedar
Biomarkers of Cardiovascular System 265
Biomarkers of Kidney Injury 267 • Biomarkers of Gut Failure 269
Biomarkers of Brain Damage and POCD 272
Journal Scan 278

Surender K Malhotra, Krishna HM, Chand Sahai, Rakesh Kumar
Index 291
CHAPTER 1
Immune Modulating Diet in
Critically Ill: Myth or Reality
Subrat Dam, Vinod Kalla
INTRODUCTION
Nutritional support in the critically ill is an important therapeutic intervention
to prevent metabolic deterioration, loss of lean body mass and improve clinical
outcome. It is especially challenging to manage these patients because of the
evolving metabolic and inflammatory response which occurs with the progression
of the underlying disease, and the difficulty in tailoring nutritional support in
this constantly evolving environment. Over the years, attempts have been made
to use nutritional formulations, not only as a supportive measure but also as a
therepeutic modality to improve patient outcome. Evidence has evolved with
regard to the composition, route and timing of dietery formula. However, despite
rapid progress in technology and delivery systems, nutritional management in
the critically ill remains a clinical challenge because of heterogeneity among
critically ill patients, difficulties in assessment of deficits and lack of uniformity
in implementation.
ENTERAL VERSUS PARENTERAL NUTRITION

Critically ill patients are often malnourished and accumulate an energy deficit
due to their inability to feed and continuing losses due to the accompanying
catabolic response. Initially, there was heavy dependence on total parenteral
nutrition (TPN), the intravenous route being considered ideal for replacing
nutritional deficits. However, it was soon realized that TPN leads to morphologic
and functional changes by inducing a rapid decrease in intestinal blood flow
leading to villous atrophy, suppression of protein synthesis and cell proliferation
in gut mucosa.¹ Increased permeability associated with mucosal atrophy may
then lead to translocation of bacteria and their products from the lumen of the
gastrointestinal tract (GIT) to the systemic circulation.² Institution of enteral
nutrition (EN) reverses this loss of gut mucosal integrity and associated lymphoid
tissue (GALT), preservation of hepatic and pulmonary immune functions, and
reduction of inflammation and antigenic leak from the gut.³
Enteral feeding also seems to preserve IgA- dependent upper respiratory tract
immunity, which may explain the higher pneumonia rate in critically injured
patients given TPN.4 Over the years, enteral nutrition has undergone many
refinements leading to increased indications, establishment of appropriate routes
and addition of specific infusion systems and nutirents. Hyperalimentation has
2 Yearbook of Anesthesiology-6
given way to lower calorie diets. Substrates were also added to adapt to specific
situations of malnutrition and stress.
In a recent comprehensive systematic review and meta-analysis of 18
randomized controlled trials (RCTs) involving 3347 patients, Elke et al.5 observed
that though EN versus PN does not affect mortality, EN significantly reduced the
length of intensive care unit (ICU) stay and infectious complications. It was also
found to be more economical. Therefore, in accordance with the guidelines of
the Society of Critical Care and the American Society of Enteral Nutrition (2016)
on provision and assessment of nutritional support in the critically ill, EN should
be the first line nutritional therapy in the critically ill adult with a functioning
gastrointestinal tract.6
INFLAMMATION AND IMMUNE RESPONSE

Trauma, inflammation, or infection typically leads to activation of a well-geared
inflammatory response. Pro-inflammatory activation is almost immediately
followed by a reactive anti-inflammatory response, which is called the systemic
inflammatory response syndrome (SIRS). It releases both pro-inflammatory and
anti-inflammatory mediators. A wide array of cytokines, such as tissue necrosis
factor–alpha (TNF-α) and interleukin-1 (IL-1) are released which activate several
inflammatory cascades. A plethora of inflammatory and immune cells, such
as tissue macrophages, monocytes, mast cells, platelets, and endothelial cells
participate in this complex immuno-inflammatory response.7
Regardless of etiology, adaptive metabolic pathways are activated during
critical illness to divert energy substrates to vital tissues involving the sympathetic
nervous system, pituitary hormones, and anabolic hormones like insulin.8 The
metabolic response during the progression of critical illness can be delineated
into specific phases. In the beginning, the body attempts to ward off the acute
insult by a hypermetabolic response. This accelerated catabolism, which is
associated with a resistance to anabolic hormones, including insulin; helps divert
energy substrates to vital organs by bypassing insulin-dependent organs, such as
fat and muscle.9 Next comes the reactive phase of metabolic slowdown due to
lack of adequate energy supply or possibly by the direct inhibition of metabolic
pathways. Finally, if the patient recovers, his appetite returns, anabolic process
recommences and organ functions are gradually returned to normalcy. This
evolving metabolic response to stress leads to progressive increase in energy
expenditure, stress hyperglycemia, changes in body composition with depletion
of muscle mass, and psychological and behavioral problems.10,11 Nutritional
intervention thus should be tailored to specific phases of critical illness
particularly when organ dysfunction ensues, as inappropriate feeding may lead
to deleterious consequences.
IMMUNONUTRITION AND PHARMACONUTRITION

Inability to feed and energy deficit in the critically ill leads to a state of starvation.
Both, macronutrients and micronutrients get depleted during critical illness
and need to be supplemented. This depletion is associated with increased rate
of infection, impaired immune function, increased dependence on mechanical
ventilation and prolonged ICU stay. The ability of specific nutrients to modify
Immune Modulating Diet in Critically Ill: Myth or Reality 3
the stress response of critical illness led to the development of specialized

nutritional formulae called immune–modulating diets (IMD). IMD contains
pharmaceutical nutrients that have demonstrated beneficial effects on cell
function, modulate inflammation and enhance immune-function in animal
studies.12 These immuno-nutrients are added to a standard enteral or parenteral
feed in addition to proteins, carbohydrates, vitamins and trace elements. The
term ‘Pharmaconutrition’ was coined by Heyland and colleagues who postulated
that immunonutrients should be delivered in full strength in combination with or
without other macronutrients in order to have their desired effects.13
Immunonutrients which have a qualified place in critically ill, include
arginine, glutamine, omega-3 polyunsaturated fatty acids (PUFA), nucleic acids
and antioxidants, such as ascorbic acid and selenium. Advent of specialized
nutritional formulas was documented to provide benefits in a number of
randomized studies although it still remains to be determined which nutrient
given individually or collectively provides the beneficial effects.14
ROLE OF INDIVIDUAL IMMUNONUTRIENTS

Arginine
Arginine a non-essential amino acid during normal physiology, becomes
conditionally essential in the altered metabolic and inflammatory milieu of
critical illness. It is required for protein synthesis, urea synthesis (5%), and
a small proportion produces nitric oxide by the nitric oxide synthase (NOS)
enzyme system. NO, an important neurotransmitter and cytotoxic agent, is
formed by oxidation of L-arginine, by inducible nitric oxide synthase (iNOS)
in many cells including endothelium, brain, platelets, hepatocytes and by
inflammatory cells including lymphocytes, macrophages, neutrophils, and mast
cells. iNOS is expressed during inflammation by cytokines and endotoxins such
as interleukin-1, tumor necrosis factor-α, γ-interferon, and lipopolysaccharide.
Therefore, it plays an important role in wound healing, cell regeneration and
vasodilation. About 15–20 g/day arginine is produced endogenously by the
citrulline-intestinal-renal axis and on an average 5–6 g/day is supplemented by
diet. During stress and illness the endogenous production is unable to cope with
the increased demands. In the last three decades, arginine has been the subject of
intense clinical investigations for its role as an immunonutrient.15
Arginine levels vary subject to the stage of sepsis, being lowest in the earlier
stages, and mounts with the advance of sepsis to multiple organ dysfunctions.
Arginine deficiency has been detected to be more severe following major trauma.
This deficiency might be the reason behind endothelial dysfunction, severe
catabolism, impaired wound healing, and poor prognosis observed in these
patients.16
The timing of administration of arginine in sepsis seems important, as it can
be potentially harmful in patients with more severe metabolic manifestations.
This could be the reason for the greater beneficial effects of an arginine-rich
immune-modulating diet in septic ICU patients with less severe disease (Apache
II < 15).17 Likewise, adding arginine as an immunomodulator at early stage
of sepsis or in postoperative and trauma patients may impart clinical benefits.
However, it is potentially harmful if administered in septic patients with more
severe involvement.18 A meta-analysis in critically ill patients displayed evidence

of adverse effects on outcome with the use of arginine.19 Other studies have
observed comparable poor outcome in septic patients administered arginine-
supplemented immunonutrients compared to patients given a standard
formula.20
In another study, improvements in clinical outcomes, such as infectious
risks, ventilator days, ICU and hospital stay were essentially observed in surgical
patients and in patients who tolerated critical amounts of arginine. Patients
with advanced sepsis associated with shock and organ failure may be adversly
affected by the introduction of immune-modulating diet containing arginine by
escalating inflammation.21 Similarly, addition of arginine to fish oil was observed
to nullify the beneficial effects of fish oil on outcome of ICU and trauma patients
with sepsis. Diets complemented by arginine do not seem to offer any additional
advantage over standard enteral formulas.22
Arginine in advanced inflammation associated with sepsis promotes
generation of large quantities of nitric oxide whose metabolic products are
potent oxidants that damage mitochondria, increases gut barrier permeability,
and support organ dysfunction.23 Negative outcomes in various studies led to the
questionability of the effectiveness of arginine supplementation and therefore,
experts suggest against using arginine supplementation in critical ill patients, as
this may lead to higher mortality.24 On the basis of available literature and latest
evidence at present, use of arginine is not recommended in the critically ill.
Glutamine
Amino acid glutamine (GLN) is plentiful in the healthy state with large amounts
of muscular reserves. Rapid drop in glutamine levels occur in critical illness.
Studies suggest that reduced levels of glutamine in critical illness may be linked
to increased mortality.25 Immune functions are likely to be compromised by this
paucity of glutamine. This can be ascribed to the role played by glutamine, in
normal functioning of macrophages, lymphocytes, and neutrophils. Another
mechanism is increased vulnerability to oxidative stress due to lack of glutathione,
which is an important endogenous scavenger of reactive oxygen species, and
glutamine is an important substrate for glutathione.26 Glutamine is also essential
for maintaining the gut mucosal barrier and thus prevents transmigration of gut
microbes into systemic circulation. This barrier function may be compromised
with glutamine deficiency in the critically ill.27
Plasma concentration lower than 420 μmol/L has been associated with a
higher risk of mortality in adult populations.28 Extrapolated to critically ill, low
plasma glutamine concentration has been associated with poor outcome. A
morbidity disadvantage has been attributed to low levels of glutamine in critically
ill pediatric patients.29
A meta-analysis based on earlier studies on glutamine was the basis for
guidelines recommending intravenous supplementation of glutamine in critically
ill patients.30 Wischmeyer et al. in a recent study found parenteral glutamine to be
useful when given inconjunction with nutrition support in critically ill as it led to a
significant reduction in hospital mortality and hospital length of stay.31 However,
a recent Cochrane database systematic review found only moderate and low-level
evidence on reduction of morbidity with glutamine supplementation compared

to the former studies.32 Similarly, a meta-analysis including 11 studies and a total
of 1079 patients, showed no clinical benefit accrued with enteral glutamine as a
supplement in critically ill patients, with the exception of reduced hospital stay.
However, critically ill burns patients were the exception as there was significant
reduction in mortality in this subgroup of patients.33 In a recent randomized
study on more than 1000 patients, early administration of glutamine was found
to increase mortality and challenges the previous impression in relation to
glutamine in critically ill patients.34
Two large studies further contest prior guidelines and recommendations
for glutamine supplementation in critically ill patients. Reducing Deaths Due
to Oxidative Stress (REDOXS) and MetaPlus trials have shown no effects of
GLN on infectious morbidity; in truth it may be associated with increased long-
term mortality in critically ill patients.35,36 These recent publications contrary
to previous recommendations have started casting doubts on the earlier
recommendations regarding use of glutamine in critically ill patients.37
Omega-3 Fatty Acids, Gamma-Linolenic Acid and Antioxidants

There are three main pathways for the synthesis of lipid mediators: cyclo-
oxygenase, 5-lipoxygenase and cytochrome P450, by using fatty acids arachidonic
acid (AA), eicosapentaenoic acid (EPA) and γ-linolenic acid (GLA) as substrates.
Long-chain omega-6 and omega-3 polyunsaturated fatty acids (PUFA) form
the framework of cell membranes. They herald production of the hormones
‘eicosanoids’ and ‘docosanoids’, responsible for regulation of inflammation,
immunity, and platelet aggregation. Omega-6 FA produce pro-inflammatory
products derived from arachidonic acid (AA) whereas omega-3 fatty acids
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are usually anti-
inflammatory.38 Humans have inadequate capability to synthesize EPA and DHA
from alpha-linolenic acid (ALA) during basal conditions and more so during
acute, severe illness.Fish (e.g. sardines, mackerel, and tuna) is rich in these fatty
acids. Consequently, supplementation of omega-3 fatty acids in critically ill
patients necessitates administration of fish oil-based lipids.
Gamma linolenic acid (GLA) despite being an omega-6 polyunsaturated fatty
acid (derivative of borage oil) has an action similar to EPA and DHA and thus helps
in reducing inflammation. Further, it is metabolized to one-series prostaglandins
(e.g. PGE1), which stimulate pulmonary vasodilation, thus, reducing the lung
injury in acute respiratory dystrers syndrome (ARDS).39
Combination of formula feeds containing fish oil, borage oil, and antioxidants
has been documented to benefit patients with acute lung injury (ALI) or ARDS
on mechanical ventilation. In the INTERSEPT study, enterally administered EPA/
GLA was found to play a beneficial role in the treatment of early stages of sepsis by
slowing the progression to organ dysfunction.40 Another meta-analysis of clinical
trials compared an immune modulating diet containing EPA, GLA and elevated
antioxidants with a control diet and indicated a significant reduction in mortality
and significant improvements in oxygenation and clinical outcomes of ventilated
patients with ALI/ARDS.41 Similarly, enteral formula enriched with EPA and GLA
was found to be beneficial for gas exchange, respiratory functions, which led to
reduced time for mechanical ventilation along with decreased ICU and hospital
length of stay in patients with acute lung injury.42 Consensus gradually grew that
completion of early goal-directed therapy in sepsis is significantly associated with
decreased in-hospital mortality; therefore, the timing of nutritional intervention
is important in sepsis.43
In a subsequent phase II RCT of enteral fish oil in patients with ALI decrease
in pulmonary or systemic inflammatory mediators, was not evident and clinical
parameters like decrease in ventilator-free days, ICU-free days, organ failure, or
mortality did not show any positive benefit. This trial contradicts prior studies
suggesting benefit of an enteral formula containing fish oil.44
In a recent randomized, double-blind, placebo-controlled, multicenter
OMEGA study, enteral administration of n-3 fatty acids, γ-linolenic acid, and
antioxidants was compared with an isocaloric control group, which again did not
show any improvement in clinical outcomes or biomarkers of inflammation in
patients with ALI. Surprisingly, this study also showed a similar trend towards
failure as seen with other pharmaconutrients as the study suggested they could
be harmful in critically ill.45
A randomized study by Grau-Carmona et al. compared an enteral diet
enriched with EPA, GLA and antioxidants with a standard enteral diet to find the
incidence of organ dysfunction and nosocomial infections in septic patients with
ALI/ARDS. The test diet was not observed to improve gas exchange or decrease
the incidence of organ failures in critically ill septic patients with acute lung
injury or ARDS.46 In a recent study done in 2014 on a small number of patients
using EPA, GLA, DHA and antioxidants on gas exchange and of length of ICU
stay of ALI and ARDS patients, beneficial effects were observed in patients with
higher APACHE III scores. However, despite the author’s recommendation, this
study should be interpreted with caution as the study group was very small. In a
meta-analysis to settle the controversy, seven RCTs were analyzed to assess the
use of enteral ω-3 FA. Although the ω-3 FA feed was well tolerated, there was
no significant reduction in all-cause 28-day mortality, ventilator-free days, or
intensive care unit-free days between the two groups.47 Based on these recent
trials, routine use of ω-3 fatty acid-enriched nutrition cannot be recommended
before better evidence emerges to conclusively determine its effectiveness.
Selenium
Interventions directed to counteract the inflammation and oxidative stress in
sepsis using selenium is suggested by many studies. Selenium, an essential trace
element is central in the biosynthesis and function of selenocysteine containing
selenoproteins, which are the catalytic centers of most selenoenzymes.
Glutathione complex, with redox potential, consists of selenium-dependent
peroxidases and the thioredoxin reductases. Selenium has been suggested to
inhibit the expression of proinflammatory genes in immune cells and thus may
play a therapeutic role in sepsis.48 Selenium deficiency has also been correlated
with increased risk of nosocomial infections.49
Studies directed to identify these positive effects of parenteral selenium

supplementation in critically ill patients with sepsis have produced inconsistent
results. In a prospective randomized trial, parenteral selenium substitution
in patients with SIRS/sepsis led to increased plasma levels of both selenium
and glutathione peroxidase levels, but failed to reduce mortality.50 However,
addition of glutamine, selenium, or both in a standard isonitrogenous, isocaloric
preparation of parenteral nutrition showed a reduction in onset of new infections,
if selenium was used for more than 5 days.51
Mixed antioxidants added to modulate immune functions in a meta-analysis
were found to be beneficial in improving clinical outcomes such as length of stay,
infectious complications and duration of mechanical ventilation which might
reduce costs associated with critical care.52 Another systematic review assessed
mortality, infectious complications, length of hospital stay and observed its
potential benefit in critically ill adult patients.53
In a recent prospective randomized clinical trial early goal directed
administration of high-dose selenium was not found to reduce 28-day mortality.
However, glutathione peroxidase levels were enhanced without any effect on
inflammatory cytokines at any point of time in mechanically ventilated septic
patients. Selenium supplementation did reduce the occurrence of VAP, which
may have beneficial effect in optimizing healthcare resource consumption
measures.54 Despite its central role in reducing oxidative stress, the current data
does not clearly support its use in critically ill patients.
CONCLUSION
Nutrition in the last three decades, has emerged as a supportive therapy to
ameliorate, the metabolic and inflammatory response and prevent oxidative
cellular injury associated with critical illness. Early institution of EN containing
clinically sufficient macro and micronutrient has been developed as a
therapeutic approach to arrest the progress of disease, reduce complications and
also reduce cost of treatment by reducing length of stay in the hospital. Immune
modulating formulas were acknowledged as agents to modulate the immune
and inflammatory response associated with critically ill. Arginine, glutamine,
omega-3 fatty acids or a random combination of these were used in the last three
decades based on earlier recommendations. Despite its central role in reducing
oxidative stress the current data does not clearly support the use of immune
modulating diets in patients with sepsis. Current guidelines, thus, do not advocate
immune-modulating enteral formulations containing arginine and glutamine for
routine use in critically ill. Routine use of enteral formulation enriched with anti-
inflammatory lipid agents, such as omega-3 FAs, and antioxidants in patients
with ARDS and severe ALI is also not advocated because of inconstincencies in
the availble studies.
Although evidence continues to support the use of immune modulating diet
in burns and trauma patients, recent trials have failed to support their routine use
along with standard nutrients in the critically ill and hence should be avoided
until further well-conducted trials find positive results in their favor.
KEY POINTS
• N utritional support is an important supportive and therapeutic intervention in the
critically ill.
• Critical illness triggers a well-defined metabolic and inflammatory response delineated
into; hypermetabolic phase, accelerated catabolism, reactive metabolic slowdown and
finally anabolic phase of recovery.
• Nutrition should be tailored to the specific phase of metabolic response as inappropriate
feeding may lead to deleterious consequences.
• Enteral route should be preferred in all patients with functional gastrointestinal tract.
• Dietary formulations containing nutrients, such as arginine, glutamine, omega-3
polyunsaturated fatty acids, nucleic acids and antioxidants such as ascorbic acid and
selenium are called immune-modulating diets (IMD).
• IMDs were recommended as beneficial in critically ill patients as they were seen to
boost immunity.
• Routine use of IMDs in all critically ill patients is controversial as recent meta-analysis
and clinical trials fail to show their beneficial effects.
• IMDs may have a beneficial role in the care of patients with burns and trauma.
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CHAPTER 2
Medicolegal Issues in Anesthesia
Sunila Sharma
INTRODUCTION
“Is the law anti-doctor? Is such fear justified?” Justice MB Shah, former Judge,
Supreme Court of India and President National Consumer Disputes Redresssal
Commission in his Foreword to the first edition of my book entitled “Law and the
Doctor”1 wrote:
“It is a total misconception to hold that the law is ‘anti-doctor’. Since years, for
medical negligence, suits were filed for damages or a prosecution was launched in
case of criminal negligence. By enacting the Consumer Protection Act, 1986, only
an additional redressal fora was constituted. Law on the subject remains the same.
Increasing awareness on the part of the public makes the difference and not the fora
constituted under the Consumer Protection Act, 1986.”
‘Anesthesiology’ is a human intensive specialty of medicine that thrives
primarily on the physical presence of trained doctors and their vigilance during
administration of an anesthesia affected by fatigue, sickness or distractions while
working. They may become prone to monitoring deficits and make wrong decisions
that end up in adverse events, the worse of which are hypoxia, cardiorespiratory
arrest and cerebral damage. During litigations, anesthesiologists are often blamed
for conducting inadequate preanesthetic assessment (PAC) and using wrong
technique of anesthesia and administering wrong doses of anesthetic drugs.
They are also sued for medical negligence along with the surgeons for the surgical
mishaps despite adequate anesthetic care. Till date, the clear-cut demarcation of
the duties for surgeons and anesthesiologists do not exist. Time is ripe to do so at
the earliest and propagate such information to the masses.
COMMON CAUSES OF LITIGATIONS

The process of patient’s surgical journey and implied safety begins from the
acceptance of the patient for surgery under an anesthesia after adequacy of
patient’s pre-anesthetic check up (PAC) followed by preoperative stabilization,
intraoperative monitoring and postoperative care. Anesthesiologists and
surgeons are expected to identify the correct patients in the preoperative area
and before induction of anesthesia asking their name, type and site of proposed
surgery and history of allergy and reconfirmation with their wristbands and case
files. This exercise, if not followed in principle and spirit, can result in wrong
patient being operated for wrong surgery, which is viewed as negligence under
the legal doctrine termed as “Res ipsa loquitur”, which means “The thing speaks
Medicolegal Issues in Anesthesia 13
for itself”. In such cases, the defendant doctor is unable to prove that the accident
did not occur due to his/her negligence.
Complications are inherent to all procedures or actions performed by human
beings and are attributed to have occurred either due to individual’s errors or
mistakes of others and patient factors. They may be anticipated due to existing
comorbidities of the patient or may happen unexpectedly after major blood
vessel injury or slippage of stitch or surgical clamp causing acute hypotension,
myocardial or cerebral hypoxia that affect postoperative recovery and anesthetic
outcome. Common causative factors are enumerated in Table 2.1.
Post-anesthetic recovery may be uneventful in majority of the patients but,
in certain cases, could be predictably or unexpectedly delayed and the patient
may need ventilatory support till full recovery. Rarely, the patient may not wake
up at all and remain vegetative for days, months or for life. Nonrecovery from
anesthesia in ASA grade 1 or 2 patients has the potential to attract litigation as
well as maximum claim for possible dereliction of intraoperative care by the
anesthesiologist.
LEGAL ASPECTS OF ANESTHESIA

A malpractice claim is a demand for financial compensation for injuries that result
from medical care. The malpractice risks were identified using closed claims
by the National Association of Insurance commissioners during closed claims
studies in 1974. The anesthesiologists comprised of 3% of insured physicians
but accounted for 11% of total dollars paid for the patient injury. Of these, 90%
payments involved care below the standard. Thus in 1980s, the professional
liability insurance costs of anesthesia providers rose dramatically.2
Most of the preventable incidents following administration of anesthesia
involved human error (82%), with breathing-circuit disconnections, inadvertent
changes in gas flow, and drug-syringe errors being frequent problems
(Table 2.1). Overt equipment failures constituted only 14% of the total number of
Table 2.1 Causative factors for perioperative complications

Anesthesia-related • Inability to intubate or ventilate
• Endobronchial migration of the endotracheal tube
• Gastric aspiration
• Drug anaphylaxis or overdose
• Cardiac arrhythmias and hypotension
• Acute pulmonary edema
• Accidental pneumothorax during nerve block or central line insertion
• High spinal anesthesia
Surgery-related • Massive hemorrhage due to accidental vascular injury
• Common bile duct injury
• Inexperience of the surgeon
• Prolonged surgeries
Equipment-related • Unnoticed disconnections, leakages or malfunction
Manpower-related • Inefficient or inadequate number of experienced anesthesiologists
Patient-related • Inadequately controlled heart disease, hypertension, cardiac
arrhythmias, heart failure, heart block, diabetes, thyrotoxicosis,
hypothyroidism, electrolyte imbalance, renal failure, sepsis, etc.
preventable incidents, but equipment design was indictable in many categories

of human error, as were inadequate experience and insufficient familiarity with
the equipment or with the specific surgical procedure. Other factors frequently
associated with the incidents were inadequate communication among personnel,
haste or lack of precaution, and distractions.3
The UK National Audit Project reported that out of a total of 7,00,000 spinals,
epidurals and combined spinal-epidurals undertaken annually, permanent
harm results in up to 1 in 25,000 cases.4 Anesthesia-related claims accounted for
2.5% of all claims and 2.4% of the value of all claims in UK. They were related
to regional anesthesia, inadequate anesthesia, obstetric anesthesia, airway and
dental damage, drug allergies, patient positioning, consent issues, invasive
lines for central venous pressure measurement and even peripheral venous
cannulations.5 Common allegations against the anesthesiologists from the
literature and American Society of Anesthesiologist Closed Claim Project (ASA-
CCP) 1990-2009 are compiled in Table 2.2.3,4,6-20
Closed claims studies suggest that errors in judgement and performance
occur and can have serious consequences. Monitors and alarms are invaluable
and familiarity with use of alarms and recommended pre-use equipment checks
are essential for anesthesiologists.
DOCTOR-PATIENT RELATIONSHIP
The societies all over the world has witnessed a huge change in their thinking
processes with the explosion of information about every aspect of health on the
click of a button. This has led to a sea change in the attitude of patients who are
gradually moving from the acceptance of the traditional paternalistic attitude
of the doctors to the relationship based on the contract. Consent process is an
evidence of that contract based on provision of adequate information about the
proposed treatment, procedures, risks and alternatives and is challengeable
under the law.
Two types of situations are prevalent in anesthesia practice:
1. When an anesthesiologist is called for professional work by the surgeons or
nursing homes, or employed by a hospital, the whole responsibility of the
patient lies on them.
2. When the patient approaches the anesthesiologist, the responsibility lies on
the anesthesiologist for his/her actions.
Anesthesiologist liability to the surgical patients begins from their first
consultation during PAC that binds them into a doctor-patient relationship.
This relationship is built on mutual trust and communication which confers
on them various duties beginning from proper preoperative assessment to
administration of an anesthetic and postoperative care. Traditionally, the
work pattern of the group of anesthesiologists in a departmental setting entails
unpredictable individual duty patterns from PAC to OTs, night duties and offs
due to which it may not be possible that the anesthesiologist who examined and
communicated with the patient initially would also conduct the anesthesia. This
system is known to bring some gap in the professional relationships with the
patients unlike surgeons, who follow their patients right from OPD till discharge
and followups.
Table 2.2 Allegations against anesthesiologists compiled from ASA-CCP data

[1990 to 2009]3,4,6-20
Closed claims %
Preoperative • Performance of inadequate pre-anesthetic check-up
• Not waiting for the investigation results before
administration of anesthesia
• Failing to perform or repeat certain pre-surgery/pre-
procedure investigations near the time for procedure
• Missing to look into the patient’s files for abnormal results
before administration of anesthesia for repeat surgery
• Not confirming for arrangement of blood and blood
products before induction of anesthesia for surgeries,
where major blood loss is anticipated
• Not following the recommended processes and
established protocols of anesthesia
• Administering anesthesia under alcohol or drug abuse
• Failure to honor patient request of no resident to be
involved, failed to discuss a specific complication or
change in anesthesia plan
Intraoperative • Faulty judgment in choice of technique of anesthesia
• Airway injury (Gas delivery device problems with 8%
anesthesia machine-2%, breathing circuit-39%,
gas supply lines, vaporizers and ventilators-49%,
misconnections, disconnections)
• Pneumothorax 4%
• Drug errors, administering the drug to which patient was 4%
allergic, mislabelled syringes
• Burns from warmers /cautery 6%
• Respiratory events: Inadequate ventilation-7%, 45%
oesophageal intubation-7%, difficult intubation-12%
• Aspiration pneumonitis 25%
• Cardiovascular event 3%
• Not protecting the patient from occurrence of nerve 21%
injuries, tooth injury or pressure ulcers
• Eye injuries 5%
• Awareness emotional distress. 2% of all claims involved 5%
cases with recall of events under GA, substandard
care because of inadequate anesthesia, failure to turn
on vaporizer, vaporizer malfunction or inadequate
induction dose
• Backache 5%
• Central venous catheter complications (1990–2004) 13.5%–16.5%
• Death/brain injury 44%
• Unexpected cardiac arrest during spinal anesthesia 30%
• Complications associated with peripheral nerve blocks
Postoperative • Visual loss (81% submissions to postoperative visual loss 7%
registry were related to ischemic optic neuropathy due
to direct pressure on globe 13%, emboli, low retinal
perfusion pressure or regional block in 2.6% )
Contd…
Contd…
Closed claims %
• Inadequate follow-up care 7%
• Post-dural puncture headache 8%
• Pneumothorax 21%
• No pain relief 8%
• Meningitis 6%
• Infection at injection site 4%
• Death and Brain Damage due to opioid-induced 77%
respiratory depression (RD)
Obstetric • Maternal death due to failure to secure an airway 25%
event claims
• Back pain, emotional distress 47%
• Neonatal deaths 27%
• Newborn brain damage 14%–22%
• Newborn injury 1.5%
Trauma • Emergency anesthesia (34% ASA 3–4) 18%
Anesthesia
• Claims for aspiration, brain damage, difficulty of
intubation, intraoperative awareness, standard of care,
inadequacy of records
• Trauma anesthesia care (1987-1999) 4.8%
Regional • Cardiac arrests 30%
anesthesia
claims
• Pain management 23%
• Intravascular injury 10%
• Eye loss 2.6% of 22%
perineural injury
claims related
to RA]
Pediatric • Cardiac arrest during maintenance phase (cardiac arrest 67%
perioperative registry) 56% were due to cardiovascular causes, electrolyte
cardiac arrest imbalance, fluid therapy, hemorrhage, cardiopulmonary
bypass.
• Medication events (wrong dose) 53%

*ASA-CCP—The American Society of Anesthesiologists-closed Claims Project
Doctor-patient relationship builds a legal contract.21 An anesthesiologist

once deemed to be under this relationship, is bound by two important duties to
the patients:
1. Duty of care
2. Standard of care
Duty of Care
This is based upon the contract, real or implied between the doctor and the
patient. This contract binds both the doctor and the treating institution. Every
doctor has a duty to exercise due care towards the patient, whom he/she accepts
to treat irrespective of payment of the professional fees to the doctor by the
patient. Other duties that arise from ‘Duty of care’ are:
i. Duty to explain by giving information to the patient, who has to decide
whether to undergo an operation and his choice of anesthesia technique.
ii. Duty to provide safe anesthesia by:
• Thorough PAC, preparation and planning anesthesia technique
• Using anesthesia machine, which is fully functional and well maintained.22
• Using monitors which warn of unsafe gas mixtures, inadequate oxygen
saturation, inappropriate ventilation, cardiac arrhythmias, heart rate, blood
pressure and temperature.
• Checking the equipment particularly those which have been serviced recently.
• Being physically and mentally active, ensuring high quality service.
• Using techniques that are currently practiced and safe by keeping oneself
updated.
• Monitoring the patient vigilantly so as to promptly detect and treat the adverse
events.
• Keeping an adequate written record which resembles a “Black box” like
evidence, and can be shown in times of need.
iii. Duty to tell when things go wrong. It is the duty of the surgeon and the
anesthesiologist to inform the patient’s attendants about the complication
that occurs inside the operation theater. It may be done slowly after building
up the scene and once the relatives are mentally prepared, then the adverse
incident may be gently revealed.
The Duty of Care is also owed by the treating institution to provide adequate
and trained hands and all necessary latest functioning equipment. Institutional
vicarious liability can arise for the negligent acts of its employees and also through
a failure to provide sufficient staff or equipment.
Breach of duty of care may be deemed to have occurred due to the following acts
of omission or commission on the part of the anesthesiologist and is punishable
under Sec. 304A IPC of Indian Law:
i. Nondisclosure of inherent or potential dangers involved during or after the
chosen technique of anesthesia.
ii. Unrevealed risks materialize and cause injury.
iii. A reasonable patient would have deferred operation if he had known of the
risks involved.
Failure to fulfill the duty of care occurs if a patient suffers damage due
to dereliction in the duties by the concerned doctors; a legal action may be
initiated against them and the institution any time within the period of limitation
prescribed by the consumer or civil courts of jurisdiction.
Immunity to breach of duty is considered when a doctor acts as a good
samaritan and helps an injured person during an emergency, he/she is immune
to breach of duty. But if there is an action of omission or commission by the doctor,
which is acceptable only by a minority of anesthesiologists, it may be construed
as a breach of duty.
Standard of Care
Standard of care is defined as the level at which the average, prudent and similarly
qualified providers in a given community, would manage the patient’s care under
the same or similar circumstances. The standard of care varies with the level of
healthcare facility, the quality of work and expertise of the health workers. In
far-flung places or level-1 hospitals, where proper infrastructure for administration
of anesthesia is not available, a lower standard of care is acceptable as per the
‘Locality rule of law’. However, since most of the world has now become a global
village, the locality rule may no longer be acceptable in many places. Hence, the
doctors are expected to demonstrate the skills established by their respective
specialties according to the established ‘National Standard of Care’.
In cases of medical negligence, the courts have set a pragmatic standard of
care which is flexible to the extent that it mirrors developments within medical
knowledge and caters for alteration in medical practices. It also recognizes the
fact that medical treatment is full of risks and the desired outcome may not
be achieved. In the case of specialists, the standard of care expected is higher.
[Andhra Pradesh High Court, in Pinnamaneni Narasimha Rao v Gundaxarpu
JayaPrakasu–AIR 1990 Ap 207]. A specialist is judged by the standards of his
specialty. Anesthesiologists are expected to adhere to standard practice. They
may not be aware of the latest developments but they are expected to follow the
protocols of the institution.
Minimum Monitoring Standards of Anesthesia

It was only during the year 1992, when a directive to implement the Minimum
Monitoring Standards of Anesthesia was circulated to all the Delhi government
hospitals by DGHS for the first time, at the behest of the executive committee of
the Delhi Branch of Indian Society of Anesthesiologists (ISA), for enhancing the
patient safety and uniformity in the practice of anesthesia. This was a government
initiative appreciated by all the anesthesiologists especially those who worked
as freelance practitioners in small nursing homes, where owners of the nursing
homes provided neither an anesthesia machine nor the patient monitors for the
operation theaters.
Documenting the standard of care: Anesthesia record is the primary
document, which reveals the standard of care rendered by an anesthesiologist in
case legal disputes arise. The acceptable standard of care in anesthesia in most of
the countries in the world is determined by the medical societies practicing the
specialty.
Deviations from standard of care determines the negligence claims and good
documentation helps to demonstrate in disputed cases whether the standard of
care was breached or not. If the breach results in an identifiable injury then the
damages [as monetary compensation] may be granted to the injured patient who
files a complaint.
Failure of standard of care: A doctor is judged by the standard of care prevalent
at the time of occurrence of an adverse event and not by that present at the time
of trial which could be many years later. The case of Roe and Wooley vs. Ministry
of Health UK [1954] has become a standard of reference in such type of legal
cases as the event occurred in 1948 when phenol percolated into local anesthesia
ampoule to cause paraplegia, a possibility not known at that time, hence the
anesthesiologist was not held guilty of medical negligence.
Breach of standard of care: Proof of breach of standard of care is necessary
for award of compensations in claims for negligence or malpractice. Failure to
discuss possible complications and possible change in anesthesia plan while

taking consent was identified as liability issue in 1% of ASA-CCP database
claims.12
INTRAOPERATIVE LEGAL REQUISITES
Response to an Adverse Event

If the critical event is for a short period and normalcy restored within a few
minutes, surgery can be allowed to take place. It may not be advisable to rush to
attendants to tell what happened without knowing the cause or the possibilities.
Surgeon and the anesthesiologist must ask for cross-consultation from other
specialties as necessitated by the event and must discuss about the cause and the
possible outcomes. The family should then be informed jointly from the doctor’s
chamber near the OTs.
If the critical event happens at induction of anesthesia which is serious and
resuscitation takes more than a few minutes to achieve the desired response but
the patient’s response to medical treatment is slow, then the surgical team should
consult the family members. If surgery is not an emergency, the case should
be postponed. If it is considered to be an emergency surgery, the sequence of
events that happened inside the OT should be discussed in detail with the family
members before proceeding further.
Documentation
The anesthesiologist and the operating surgeon must consult each other and
together record correct timing of all intraoperative adverse events. If there is any
difference of opinion it must be solved inside the operation theaters itself and not
in the court after few years.
The surgical and anesthetic document should not have any illegible writing or
overwriting on the error. It is recommended to cross it with a single line and enter
the correct time, date with signatures and mention the reasons for the correction.
The anesthesia chart should not be altered as it rises suspicion about hiding the
truth and there have been cases where handwriting experts have been consulted
in cases of erasure or overwriting on the chart.
POSTOPERATIVE LEGAL REQUISITES

It is the duty of the anesthesiologist to hand over the patient to the nurse or
doctor in the postoperative ward for continuity of observation and care until
the patient meets the discharge criteria from the post-anesthesia care unit. The
patient can be safely discharged if he has an Aldrete Score of 12/14 based on
his activity, respiration, circulation, consciousness and oxygen saturation. The
anesthesiologist should not undertake the next case in hurry without proper
handover to the postoperative nurse/assigned doctor.
Care of a Patient after the Bad Outcome

The doctors should maintain good contact with the family members and
allow them to vent their anger and take care of the patient continuously. They
should never hand over the patient to others and leave the scene but involve
other consultants for their opinion regarding the management. All necessary
investigations to clinch the diagnosis should be done.
The family members should be contacted at regular intervals and the progress
of the patient should be communicated by a designated consultant to avoid
different versions of the progress given by junior nurses or paramedical staff .
The patient may be shifted to a higher center if there is a necessity, and follow
up with the patient and family may be maintained to give them solace and to
gain sympathy of the patient’s attendants. If the bad outcome is due to unknown
cause, the insurance company must be notified and the expert opinion must be
sought.
STRATEGIES TO REDUCE ADVERSE PATIENT OUTCOMES

1. CMEs should be regularly attended by the doctors.
2. Guidelines and protocols for procedures should be formulated by the
associations of anesthesiology and should be readily available in the OTs.
3. Policies and procedures should be formulated by each department. They must
be practicable or the violation will be proved by the lawyers. The policies must
be reviewed regularly and amended, if necessary.
4. Displays on monitors should be believed and confirmed instead of finding
fault with them. Multiple monitors may be used for cross-checking.
5. Patient should be re-examined to find the cause of an adverse event.
6. Laboratory values and clinical condition must correlate with the incident.
7. Time should be spared by all concerned to listen to the patient or his family
members.
ELEMENTS OF MEDICAL NEGLIGENCE

There are four elements to determine a medical negligence of the doctor:
1. Duty of care
2. Standard of skill and care
3. Breach of duty
4. Damages or injuries.
The Tort of negligence requires a complainant to show first that a duty of
care was owed to him by the doctor and there was foreseeability of harm by the
doctor and there was breach of care, which resulted in injuries. To determine
the quantum of compensation to be awarded to the complainants, the courts
determine the link between the breach of duty and the injury.
The doctor is held guilty of negligence when even though he doesn’t desire
to produce the adverse events, he acts in an indifferent or careless way in
attending to the patient. A common example of an inefficient monitoring by an
anesthesiologist is of indulgence in chatting and tweeting on the social media
about the same patient a little while before a major adverse event happened to
him, which proved his negligence.
As a rule, the burden of proving negligence of the medical practitioners lies
on the complainants but if the injuries occur inside the operation theaters, the
burden of proof shifts from the complainants to the doctors and personnel
working inside the operation theaters, to explain the course of events that
happened during anesthesia, behind the four walls of the OT, where the patients’
relatives had no access.
In anesthetic practice, there are two types of cases for legal action:
1. But for: The injuries would not have occurred but for the anesthetic procedure.
2. Substitute factor: The procedure need not be the only factor in causing injury.
PROFESSIONAL LIABILITY
The professional liability of medical professionals covers different aspects:23
• Contractual liability determined by looking at the consent process that
happened between the doctors and the patients/relatives prior to the conduct
of any invasive procedure beyond a general physical examination.
• Tortuous liability entails a civil liability, which holds a physician responsible
for failing to protect the patient from infliction of any harm due to wrong
action. This involves looking at the consequences of the act and awarding
of financial compensation to sufferers general damages for pain, suffering,
anxiety and special damages for medical expenses, future expenses, loss of
wages and rehabilitation costs.
• Punitive liability deals with the physicians, who violate rules and regulations
of medical practice, even if there is no subsequent harm to the patient. The
indemnity insurance may not cover these.
• Disciplinary liability is held where a physician is found to have failed to meet
the professional standards, requirements and ethics and is dealt by issuing
administrative warning or prohibiting the physician from medical practice
and withdrawal of his medical license.
• Criminal liability: The criminal liability is not held for doctors since the
supreme court’s historic judge ment on the issue in Dr Suresh Gupta vs. Govt.
of NCT of Delhi and ANR on 4th August, 2004. Appeal (CrL) 778 of 2004. SC
held that doctors have no intention to kill a patient hence they cannot be
charged under that law”.
Law determines the liability of doctors through the following sources:
Testimony of witness of the adverse event: Hence a copy of the document containing
the testimony must be acquired soon after the accident by the anesthesiologist.
Testimony about the practice pattern of the anesthesiologist such as preuse
machine checks is also very useful for decision making by the courts.
Expert witness testimony: Judges may be laymen in medicine but there are
experts who assist them to reach a decision based on their inputs and results of
their investigations.
The proof of innocence is judged by Bolam principle which prevails in legal
judgements in India. It states that:
“A doctor is not held negligent if he acts in accordance with a practice accepted
as proper by a responsible body of medical professionals skilled in that particular
art particularly because there is a body of medical men skilled in that particular
art, particularly because there is a body of opinion that takes a contrary view”
[Bolam v Friern Hospital Management Committee. 1951;2 AII ER 118]
TIME LIMITATION AND COURT JURISDICTION24

Cases of medical negligence are tried under the tort law in the civil courts or
Consumer Protection Act [CPA]1986 in the consumer courts to protect the
consumers [patients] and safeguard their rights by rendering rapid redressal
to their complaints. The consumer courts are located at the state level, district
level and national level to hear both the patient and medical parties and render
decisions based on medical data submitted for the case to them. Both parties, if
dissatisfied with the decision of the lower courts, can appeal to higher courts as
per designated procedures. Complainants need to be aware of the limitations of
the law as per the time of two years for filing a case of medical negligence after
discovery of the patient injury and also of the jurisdiction of the court to handle
the case filed before it.
OUTCOME OF A COURT TRIAL

For closing a legal case, the options available for both parties include outside
court settlement, court settlement if proved and asset protection in which case
the insurance company escapes or pays partially. Doctors’ defenses to liability
include:
Consent: What is consented is not actionable [Volenti non fit injuria]. This fact is
aptly illustrated by the surgical operations which are performed under anesthesia
with the patient’s written consent instead of just a verbal assent.
Inevitable accident: Doctor is not liable if the act that caused the alleged harm
could not have been avoided by an ordinary care.
Remoteness of damage: The complainant cannot recover damages if there is
no causal connection between the defendants alleged act and the harm that is
complained of.
Act of God: If injury happened despite best precautions, resuscitation and care.
One should prepare well before deposition in the court. It is advisable to reply
to the legal notice within the allocated time period on advice of legal consultants.
Before deposition, the anesthesiologist must know the events that led to the
bad outcome. He must seek opinion of senior colleagues and submit authentic
anesthesia literature to the courts in support of his views and actions. The
answers should be brief—by yes or no and correct, without explanations. If the
anesthesiologist is not happy with the lawyer appointed by insurance company,
because of an evident conflict of interest between the doctor’s defense and the
company’s money, he/she should seek the services of a separate lawyer. Medical
indemnity from a good insurance company with a good background helps. An
agent should not be entrusted the work of selecting the company at a cheaper
cost. The agreement contents with the company should be read thoroughly.
CONCLUSION
Errors in judgment and performance are known to occur and can have serious
legal consequences. A thorough PAC and patient optimization, familiarity with
equipment and preuse equipment checks can prevent anesthetic accidents. Clear
demarcation of the professional responsibilities and the duties of care for both
surgeons and anesthesiologists is essential for easing out the process of fixing
liabilities in today’s litigatory scenario. Doctors must keep abreast with times
and follow approved methods of patient management. No machine can replace
“Vigilance” and “Competence” of an anesthesiologist.
KEY POINTS
• Anesthesiology is a human intensive high-risk specialty but perceived to be non-
therapeutic.
• Anesthesiologists are specialists, hence law expects a high standard of patient care
during conduct of their professional work.
• They are held fully responsible for anesthesia and its consequences in medicolegal
disputes.
• Locality rule is not applicable for the specialists.
• Anesthesiologist’s duties to the patient’s care include ‘Duty in Tort’, ‘Duty in Contract’
and ‘Duty to Explain’.
• Good perioperative anesthetic documentation is essential.
• All intraoperative adverse events must be discussed with the surgical team and
recorded.
• Testimony of an ‘Expert Witness’ carries weightage during legal trials.
REFERENCES
1. Sharma S. Law and the Doctor. Paras Medical Publisher. ISBN:978-81-8191-331-9.
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2. MacRae MG, Pred RN. Closed claims studies in anesthesia: A literature review and
implications for practice. Rochester, New York [https;//www.Aana.com].
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monitoring study: an analysis of 2000 incidents. www.ncbi.nic.nlm.nih.gov/
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4. Levy DM. Anaesthesia-Medicolegal issues in perioperative care. 2014; dmlevy@nhs.
netAvMA.
5. Forrester AC. Mishaps in anaesthesia. Anaesthesia. 2008;14(4):388-99.
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claims against the NHS in England 1995–2007. Anaesthesia. 2009;64(7):706-18.
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human factors–Qual Saf health Care. 2003;11(3):277-82.
8. Caplan RA. Informed consent: Patterns of liability from the ASA closed claims project.
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anesthesia. AANA J. 2002;70:97-104.
10. Chadwick HS. Obstetric anesthesia closed claims update II. ASA newsletter.
1999;63:12-5.
11. Davies JM. Closed claims project focuses on 3 decades of obstetric complications,
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closed claims project. ASA newsletter.1995;59:9-12.
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from gas delivery equipment: a closed claims analysis. Anesthesiology. 1997;87:741-8.
14. Bhonanker SM, Posner K, Cheney FW, Caplan RA, Lee LA, Domino KB. Injury
and liability associated with monitored anesthesia care; a closed claims analysis.
Anesthesiology. 2006;104(2):228-34.
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newsletter. 2000;64:10-2.
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nonoperative setting. ASA newsletter. 2001;65:12-5.
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20. Caplan RA, Ward RJ, Posner K, Cheney FW. Unexpected cardiac arrest during spinal
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Joga Rao SV (Ed). Distance Education Department, National Law School of India
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programs/crna/agm/.
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Anesth. 2006;18(4).
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Chandigarh, 1996.
CHAPTER 3
Regional Anesthesia in Children
Santhanam Suresh, Vanessa Ng, Amod Sawardekar
INTRODUCTION
Regional anesthesia in the pediatric population is common in the setting
of pediatric anesthesia due to the increased use of ultrasonography,
nerve stimulation, and landmark based techniques.1,2 The introduction of
ultrasonography allows the placement of peripheral nerve blockade with greater
ease while children are anesthetized. The increased availability of point of care
ultrasounds is creating additional opportunities to complete nerve blocks. It is
well accepted within the field of pediatric anesthesia that regional anesthetic
techniques are done while children are anesthetized. While the literature
assessing evidence for the quality and safety of utilizing ultrasonography in
regional anesthesia has started to arise, the pediatric regional anesthesia
network (PRAN) has demonstrated the safety and efficacy of many regional
anesthesia techniques from data gathered.3 Case reports and correspondence,
in addition to published case series and clinical studies add to the growing body
of evidence supporting use of ultrasound in children.
UPPER EXTREMITY BLOCKS

Peripheral regional nerve blocks performed on the brachial plexus are useful
in children undergoing upper extremity surgical procedures. Various locations
of the brachial plexus exist allowing for the clinician to choose the optimal site
based on surgical procedure as well as patient criteria. These brachial plexus
sites include the axillary, infraclavicular, interscalene, and supraclavicular
approaches. The use of ultrasound provides anatomical location of structures
that are used to guide needle placement. While the supraclavicular approach
is the most common upper extremity block to be performed in children, the
increasing utilization of ultrasonography in regional anesthesia allows blockade
of the brachial plexus with ease at any location safely and effectively.
Axillary Block
Anatomy and Indications
An axillary approach allows for analgesia of the elbow, forearm, and hand. With
a single needle insertion, the radial, ulnar and median nerves may be blocked at
this location (Fig. 3.1). The radial nerve is anatomically posterior to the axillary
Fig. 3.1: Ultrasound image showing relationship of median nerve (MN), ulnar nerve (UN)
and the radial nerve (RN) with the axillary artery (AA)
artery and the ulnar nerve is located anterior and inferior to the artery. The
median nerve is anatomically anterior and superior to the axillary artery. Of note,
the neurovascular sheath in the axilla does not contain the musculocutaneous
nerve, located between the biceps brachii and coracobrachilias muscles, and
must be blocked by a separate needle insertion.
Technique
Axillary blocks using ultrasound in the pediatric population are not well
characterized in current literature, however multiple approaches may be adapted
for children from established adult techniques.4 The technique utilizes an out-of-
plane approach with the ultrasound probe placed in a transverse plane to the
humerus. Circumferential spread of local anesthetic around the neurovascular
bundle is achieved by several injections with subtle needle repositioning.
The needle directional movement should be carefully completed with use of
ultrasound as the axillary sheath is superficially located.
Complications
Infection, hematoma formation, neural injury, and intravascular injection are
possible complications of the axillary nerve block. The use of ultrasound guidance
for real time visualization may aid to decrease the risk of these complications.
Interscalene Approach
Blockade of the trunks and roots of brachial plexus via the interscalene block
results in analgesia of the shoulder and proximal arm. At this location the plexus
is located deep to the sternocleidomastoid (SCM) muscle and is flanked by the
Regional Anesthesia in Children 27
Fig. 3.2: Ultrasound image showing deep seated C5, C6 and C7 nerve roots under
sternocleidomastoid (SCM) and between anterior (ASM) and middle scalene (MSM) muscles
anterior and middle scalene muscles. The C5, C6, and C7 nerve roots are seen
between the anterior and middle scalene muscles (Fig. 3.2). The interscalene
block may be done in children undergoing surgical procedures of the proximal
humerus or shoulder.
A limited number of case reports have been published regarding the safety
of placing interscalene brachial plexus catheters in children and adolescents
undergoing shoulder surgery.5 Continuous peripheral nerve blockade (CPNB)
at the interscalene level has been successfully utilized in children to manage
postoperative pain after tumor resection from the proximal head of the
humerus.6,7 Use of ultrasound-guided interscalene catheters in children has been
described as an easier and safer alternative to using nerve stimulation, resulting
in fewer complications when performed by experienced practitioners.
Technique
The ultrasound probe is placed at the level of the cricoid cartilage at the
posterolateral aspect of the SCM. The interscalene groove, which is made up on
either side by the anterior and medial scalene muscles are found lateral to the
subclavian artery and deep to the SCM. The neurovascular bundle of C5, C6, and
C7 nerve roots lie within the interscalene groove. Although nerve stimulation may
be equally efficacious in performing the brachial plexus block at this location, the
total amount of local anesthetic required may be decreased under the guide of
ultrasonography.
Complications
A successful block of this nature is often accompanied by Horner syndrome,
recurrent laryngeal nerve block, and hemidiaphragmatic paralysis on the
ipsilateral side of the block. These clinical symptoms should not be mistaken for
complications but rather as expected. Caution should be taken when considering

the use of the interscalene block in the pediatric population as potential risks of
pneumothorax, intrathecal injection, and vertebral artery injection exist.
Supraclavicular Approach
The brachial plexus may be blocked in the supraclavicular fossa with subsequent
analgesia provided to the elbow and upper arm. The trunks and divisions of the
plexus are located anatomically anterolateral to the subclavian artery (Fig. 3.3).
Despite the known efficacy of single-injection supraclavicular nerve blocks,
limited data exists regarding continuous supraclavicular blocks in children.8
CPNB with supraclavicular catheters are typically used to provide longer duration
of postoperative analgesia for pain related to upper extremity procedures,
however care must be taken to avoid accidental catheter dislodgement secondary
to neck movement.
Technique
Few techniques have been specifically described in the pediatric population but
can be extrapolated from adult literature.9 The ultrasound probe is positioned
just above the superior border of the mid-clavicle. The subclavian artery should
appear as the pulsatile hypoechoic structure and must be the first structure
identified. An in-plane approach is utilized to guide the needle in the direction
of the brachial plexus, above the first rib and just superior and lateral to the
subclavian artery. Needle guidance in a lateral to medial direction allows the
brachial plexus to be reached prior to the subclavian artery avoiding vascular
puncture and intraneural injection.
Fig. 3.3: Ultrasound image showing the anterolateral relationship of trunks and divisions
of brachial plexus with the subclavian artery (SA) in the supraclavicular fossa
Complications
Potential complications include infection, hematoma, and intravascular
injection. Furthermore, as the lung parenchyma lies medial to the first rib,
completion of the supraclavicular block can result in an increased risk of an
ipsilateral pneumothorax. For this reason, real time visualization of the needle
tip and shaft during placement of the block with ultrasound may prevent such
morbidity.
Infraclavicular Approach
The infraclavicular block provides analgesia similar to that of the supraclavicular
block. Visualization of the brachial plexus cords occurs just below the coracoid
process. Medial to the cords lie the axillary artery and vein while anterior to the
neurovascular bundle lie pectoralis major and minor (Fig. 3.4). On ultrasound,
the lateral cord of the plexus is seen as a hyperechoic structure while deep to
the axillary artery is the posterior cord. Due to its location between the axillary
artery and vein, the medial cord may be challenging to identify. Safe and effective
means of controlling acute pain in the pediatric population using a continuous
infraclavicular nerve blockade following radial osteotomy and simplified skin
fixation procedure has been described.10,11
For moderately painful upper limb surgery, continuous infraclavicular nerve
blocks have significantly reduced pain and opioid needs in patients.12 In adults,
the combination of a continuous local anesthetic infusion with boluses have
shown to provide better analgesia in this setting while reducing oral analgesics as
compared with basal or bolus only regimens, this may be difficult to accomplish
in younger patients unable to communicate their discomfort.13
Fig. 3.4: Ultrasound image showing relationship of axillary artery (AA) to medial (MC),
lateral (LC) and the posterior (PC) cords of the brachial plexus for infraclavicular block
Technique
Multiple approaches to the infraclavicular block are described in children. Most
commonly, a lateral approach is utilized with ultrasonography. The axillary artery
is identified with the ultrasound probe in a transverse position below the clavicle.
The cords of the brachial plexus are contained within the neurovascular bundle.
An out-of-plane technique is used to advance the needle to the plexus with
care to avoid the vascular structures. Alternatively, the probe can be positioned
parallel to the clavicle in a parasagittal plane and the needle can then be directed
in a cephalad direction toward the brachial plexus. When placing a CPNB, the
catheter can be positioned with either a nonstimulating or stimulating technique.
The catheter is checked for inadvertent intravascular placement and secured to
the chest.
Complications
Hematoma, infection, and intravascular injection are possible complications
of the infraclavicular nerve block. The cervical pleura is located within close
proximity to the brachial plexus and at this position the risk of a pneumothorax
still exists.
TRUNCAL BLOCKS
As laparoscopic and minimally invasive surgical techniques in pediatrics have
increased, so have the use of truncal blocks.14 Much of the described technical
aspects and data are based on extrapolated from adult literature and practice.
Ultrasound guidance has not only increased the ease of completing truncal
blocks but also their effectiveness and safety.15
Transversus Abdominis Plane Block

Anterior abdominal wall analgesia via the transversus abdominis plane (TAP)
block is most commonly employed in procedures such as laparoscopic port
placement and abdominal incisions.16 The clinician should be aware that this
delivers postoperative analgesia but not surgical analgesia.
Anatomically, the three muscle layers, the external oblique, internal oblique,
and transversus abdominis lie lateral to rectus abdominis muscles (Fig. 3.5).
Within the internal oblique and transversus abdominis muscle is an area known
as the TAP plane. The thoracolumbar nerve roots (T8-L1) which provide sensory
innervation to the muscles and skin of the anterior abdominal wall and are found
in this TAP plane.17
Continuous analgesia by means of a catheter allow for the TAP blockade to be
prolonged by continuously infusing local anesthetic with subsequent decrease
in supplemental systemic opioid consumption. Although there is a paucity of
data in the pediatric population on the utilization of continuous TAP catheters,
an alternative to neuraxial anesthesia may be afforded by this technique. In
patients with pre-existing neurological deficits or severe spinal deformities,
reports have been published regarding excellent postoperative analgesia via the
administration of low dose, low concentration local anesthetic infusions by way
of TAP catheters.18
Fig. 3.5: Ultrasound image showing external oblique (EO), internal oblique (IO) and
the transversus abdominis (TA) muscles. Area between internal oblique and transversus
abdominis is the plane for TAP block
Technique
Needle guidance and placement of local anesthetic in the TAP plane may
be achieved with an in-plane approach using ultrasonography. The rectus
abdominis is identified by placing the ultrasound probe lateral to the umbilicus.
Movement of the probe laterally to the rectus allows for visualization of the three
muscle layers of the abdominal wall, the external oblique, internal oblique, and
transversus abdominis. Using an in-plane technique the needle is advanced to
the TAP plane. Upon injection, a pocket of local anesthetic can be created where
the nerves traverse.19
Under ultrasound-guidance, TAP catheter placement can be done by
advancing a needle using the described in-plane approach until the needle is
between the transversus abdominis and internal oblique muscles. The catheter
tip is localized when saline solution or local anesthetic is injected through the
needle. Expansion of the TAP plane by injecting local anesthetic solution allows
for accommodation and placement of the catheter. Securing the catheter by
subcutaneous tunneling may be done if desired.
Complications
Infection, intravascular injection, peritoneal and/or bowel puncture are potential
complications as well as catheter disconnect and/or dislodgment.
Ilioinguinal and Iliohypogastric Nerve Block

The ilioinguinal and iliohypogastric (IL/IH) nerves arise from the nerve roots of
T12 and L1 and cross the internal oblique aponeurosis just medial to the anterior
Fig. 3.6: Ileoinguinal (IL) and ileohypogastric (IH) nerves are seen as oval structures between
internal oblique and transversus abdominis muscles just medial to the anterior superior iliac
spine
superior iliac spine (ASIS). Analgesia afforded by the IL/IH nerve block allow for
surgical procedures in the inguinal area and anterior scrotum. Relief comparable
to that of caudal blocks for inguinal procedures have been noted with successful
IL/IH nerve blockade.20,21
Technique
The ASIS and the umbilicus are located and with ultrasound probe placed midline
the three abdominal muscle layers are identified (internal oblique, external
oblique, and transversus abdominis). The external oblique muscle layer may be
aponeurotic at this location giving the appearance of only two muscle layers. 22,23
The IL/IH nerves appear as ovular structures between the internal oblique and
transverse abdominal muscles (Fig. 3.6). Using an in-plane approach the needle
is inserted from either a medial or lateral approach and directed toward the
IL/IH nerves. The local anesthetic volume required to anesthetize both nerves
is reported to be significantly less with the utilization of ultrasonography as
compared to nonimaging techniques.20
Complications
Rare but potential complications include intravascular injection and bowel
puncture, as well as femoral nerve palsy and pelvic hematoma.
Rectus Sheath Block

The rectus abdominis muscle lies on the medial anterior abdominal wall
separated in the midline by the linea alba. The thoracolumbar nerves are located
Fig. 3.7: Ultrasound image for the rectus sheath block. Thoracolumbar nerves lie between
rectus abdominis muscle and the posterior sheath
in the potential space between the rectus abdominis muscle and posterior
sheath. Effective postoperative pain relief for umbilical hernia repair as well as
single incision laparoscopic surgery (SILS) can be provided by the rectus sheath
block. 24,25
Technique
Positioning the ultrasound probe lateral to the umbilicus, the muscle layer deep
to the subcutaneous tissue and anterior to the peritoneum is the rectus abdominis
muscle. Separating the rectus abdominis from the peritoneum is the posterior
sheath (Fig. 3.7). An in-plane approach is taken by the needle and directed to
the space between the rectus abdominis and the posterior sheath, where local
anesthetic is delivered.
Complications
Infection at the site of skin puncture, intravascular injection, and bowel
puncture are complications of the rectus sheath block. Real time visualization
under the guide of ultrasonography may help to decrease the possibility of such
complications.
LOWER EXTREMITY BLOCKS

Peripheral regional nerve blockade can provide complete sensory and motor
blockade to the lower extremity. Typical nerve blockade of the lower extremity
include the femoral nerve, sciatic nerve, lumbar plexus, saphenous nerve, and
lateral femoral cutaneous nerve. A combination of these blocks may be prescribed
by the clinician depending on the intended area of analgesia.
Lumbar Plexus Block

The lumbar plexus is situated deep to the paravertebral muscles and entrenched
within the psoas muscle. Upper leg and lower abdomen analgesia is provided via
the branches of the lumbar plexus (T12-L5) including the femoral, genitofemoral,
lateral femoral cutaneous, and obturator nerves. The lumbar plexus block is often
done in tandem with the sciatic nerve block to provide analgesia to an entire
lower extremity.26
Technique
Lateral decubitus positioning of the patient allows for the iliac crest and spinous
processes to be identified. The L4 or L5 transverse processes are then found
using ultrasonography. Beyond the transverse process are the erector spinae and
quadratus lumborum muscles, the psoas major muscle and the lumbar plexus.
The lumbar plexus is found within the psoas major and identification may be
challenging due to similar echogenicity to the muscle. Utilizing nerve stimulation
in conjunction with ultrasonography may be employed. Eliciting quadriceps
twitches confirm positioning adjacent to the plexus. It is important to note,
paravertebral muscle twitching can be seen upon needle insertion and should
not be mistaken for correct placement of the needle.
Complications
Complications include infection, hematoma, epidural injection and local
anesthetic toxicity. Due to the location of the plexus, retroperitoneal bleeding is
also a potential complication.
Femoral Nerve Block

The nerve roots of L2, L3, and L4 give rise to the femoral nerve and when blocked,
provides analgesia from the anterior thigh to the knee. The femoral nerve can be
visualized when the ultrasound is placed in the inguinal crease and is lateral to
the femoral artery and vein. The 3-in-1 and fascia iliaca block are also performed
in this location, however, there is a lack of evidence to support use of ultrasound
for these blocks in pediatrics.27,28
Continuous femoral nerve blockade has been safely and effectively utilized
in the children.29 A wide range exists for applicability, including children with
cancer-related pain, CRPS, as well as acute postoperative pain management.
Technique
With the patient in the supine position the femoral artery is located within the
inguinal crease. Using a nerve stimulation technique, the needle is guided in a
lateral to medial direction to evoke patellar movement or quadriceps muscle
twitch. Thigh twitching is commonly noted indicating stimulation of the sartorius
muscle, which should not be misinterpreted for quadriceps stimulation. The
femoral vein, artery, and nerve can be visualized from medial to lateral when
Fig. 3.8: Ultrasound image showing femoral nerve (N) lying lateral to femoral artery (A)
and femoral vein (V) at the inguinal crease
using ultrasonography (Fig. 3.8). An out-of-plane or in-plane approach may be

undertaken to direct needle placement to femoral nerve and circumferentially
surround it with local anesthetic.
Complications
Possible complications arise from the proximity of the femoral nerve in relation
to the artery and vein. Unintentional vessel puncture and hematoma formation
are potential complications as are nerve injury and infection at the site of needle
insertion. Associated risks of indwelling catheter placement include that of
infection, prolonged numbness, as well as catheter kinking, dislodgment and
disconnection.
Sciatic Nerve Blocks

Innervation of the posterior thigh and all but the medial part of the leg distal to
the knee is provided for by the the sciatic nerve which is formed by nerve roots
L4 to S3.30 The sciatic nerve exits the pelvis in the greater sciatic foramen and is
then courses inferior to the gluteus maximus muscle. The sciatic nerve continues
to the posterior popliteal fossa then bifurcates to form the tibial and common
peroneal nerves. In children, various locations of the sciatic nerve can be blocked
via the subgluteal, anterior thigh, or popliteal approach. Successful prolonged
analgesia with a continuous sciatic nerve blockade has been described.
Pain management for ankle and major foot surgery in children can be
accomplished by continuous sciatic nerve block.31 Common pediatric indications
include pain control for trauma, club foot repair, tibial and fibular osteotomy,
ankle exostosis and osteosynthesis, and toe or foot amputation. Fewer adverse
effects have been demonstrated with use of continuous sciatic nerve blockade
as compared to epidural anesthesia in children undergoing major ankle and

foot surgery.32 Use of ultrasonography can accurately and efficaciously facilitate
placement of sciatic nerve catheters.
Technique
With the subgluteal approach to the sciatic nerve block, the patient is placed
in the lateral decubitus position with the hip and knee flexed. The nerve can
be visualized between the greater trochanter and the ischial tuberosity deep to
the gluteus maximus muscle with the use of ultrasonography (Fig. 3.9). Success
with this block has been described with both an in-plane and out-of-plane
approach. In performing this block, nerve stimulation may be used alone or
in combination with ultrasound. When utilized, hamstring, calf, foot, and toe
twitches are anticipated. Successful continuous sciatic nerve blockade with
catheter placement has been described in children.
A sciatic nerve block via the anterior approach may be accomplished with use
of either nerve stimulation and/or ultrasonography.33 With the child positioned
supine, the leg is abducted and rotated laterally and the knee is flexed to the frog
leg position. The probe is positioned below the inguinal crease and the sciatic
nerve is seen deep and medial to the femur. In older children as the sciatic nerve
is at an increased depth, this approach may be technically challenging.
Finally, the sciatic nerve can be blocked distally at the popliteal fossa.34 With
the child in a prone position, the popliteal crease is found and the ultrasound
probe is placed above it. The popliteal artery is easily visualized and adjacent to
the artery is the sciatic nerve. Distally the common peroneal and tibial nerves
can be seen diverging from the sciatic nerve and may be blocked individually.
One may elicit calf, foot, or toe twitches at this location with the use of nerve
stimulation. Of note, the popliteal fossa approach using the same technique may
be performed but with the child in supine position with the hip and knee flexed.
Fig. 3.9: Ultrasound image for subgluteal approach to sciatic nerve (SN) seen lying under
the gluteus maximus muscle (GMM)
Complications
Complications include hematoma from vessel puncture, infection at the site of
skin puncture and catheter placement, as well as local anesthetic toxicity. When
children undergoing major foot and ankle surgery with sciatic nerve blockade
were compared to those with continuous epidural block, both techniques were
associated with good postoperative analgesia. However, less urinary retention,
less discontinuation of local anesthetic infusion, and less nausea and vomiting
were demonstrated in children with continuous popliteal nerve catheters.
Saphenous Nerve Block

The saphenous nerve provides innervation to the knee as well as the medial
portion of the leg below the knee. It is a branch of the femoral nerve, running
adjacent to the sartorius muscle traveling within the adductor canal before
continuing to the medial aspect of the knee. Blocking the saphenous nerve
proximally allows for analgesia of the anterior knee while blocking it distally
provides analgesia soley to the medial aspect of the lower extremity.35
Technique
A supine position is assumed by the patient and the leg is laterally rotated and
abducted as the ultrasound probe is positioned over the medial aspect of the
knee. The sartorius muscle is identified and juxtaposed to this is the saphenous
nerve (Fig. 3.10). An in-plane technique is utilized. The needle is directed using
this technique to the saphenous nerve, where the local anesthetic is deposited.
Fig. 3.10: Ultrasound image for the saphenous nerve block. The saphenous nerve is lying
juxtaposed with sartorius muscle
Complications
Saphenous nerve blockade complications include infection, injury to the nerve,
and hematoma formation from inadvertent arterial puncture.
CONCLUSION
Continuous peripheral nerve blocks are emerging as an effective analgesic
modality for children who have prolonged postoperative pain. The efficacy
and safety of these various techniques will likely help ease the transition to
early ambulation with enhanced pain management without the use of opioids
and their side effect profile. Regional anesthesia in children continues to make
advancements with the use of ultrasound in the perioperative setting including
the increased availability of point of care ultrasonography. The frequency with
which peripheral regional anesthesia is being utilized is persistently growing in the
pediatric population. While some studies suggest utilization of ultrasonography
may decrease the least possible dose of local anesthetic required for successful
blockade, additional studies are necessary to elucidate the complete risks and
benefits of completing peripheral regional anesthesia.36 The ultrasound has
allowed clinicians to utilize regional anesthetic techniques without regard
to the use of neuromuscular blockade when compared to nerve stimulation.
There remains an important role in regional anesthesia for nerve stimulation
and clinicians may choose either approach. Data available demonstrates
particular benefits to the use of both ultrasound guidance and nerve stimulation
in nerve blocks. Whichever technique is chosen, all means should be used to
advance regional anesthesia in children with the ultimate goal of improving the
perioperative experience for children.
KEY POINTS
• R egional anesthesia in children continues to make advancements with the use of
ultrasound in the perioperative setting.
• Ultrasonography allows accurate placement of the drug and may decrease dose of local
anesthetic required for successful blockade.
• Efficacy and safety of various regional anesthesia techniques will likely help ease the
transition to early ambulation with enhanced pain management without the use of
opioids.
• Continuous peripheral nerve blocks are emerging as an effective analgesic modality for
children who have prolonged postoperative pain.
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adolescents: A review of current literature and its application to neuraxial blocks.
anesthesiology. 2010;112:719-28.
2. Tsui B, Suresh S. Ultrasound imaging for regional anesthesia in infants, children,
and adolescents: A review of current literature and its application in the practice of
extremity and trunk blocks. Anesthesiology. 2010;112:473-92.
3. Polaner DM, Taenzer AH, Walker BJ, Bosenberg A, Krane EJ, Suresh S, et al.
Pediatric regional anesthesia network (PRAN): a multi-institutional study of the
use and incidence of complications of pediatric regional anesthesia. Anesth Analg.
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4. O’Donnell BD, Iohom G. An estimation of the minimum effective anesthetic volume

of 2% lidocaine in ultrasound-guided axillary brachial plexus block. Anesthesiology.
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5. Van Geffen GJ, Tielens L, Gielen M. Ultrasound-guided interscalene brachial plexus
block in a child with femur fibula ulna syndrome. Pediatr Anesth. 2006;16:330-2.
6. McNaught A, Shastri U, Carmichael N, et al. Ultrasound reduces the minimum effective
local anesthetic volume compared with peripheral nerve stimulation for interscalene
block. Br J Anaesh. 2010;6:124-30.
7. Fredrickson MJ. Ultrasound-assisted interscalene catheter placement in a child.
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8. De José María B, Banus E, Navarro EM, Serrano S, Perello M, et al. Ultrasound-guided
supraclavicular vs infraclavicular brachial plexus blocks in children. Paediatr Anaesth.
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9. Roberts S. Ultrasonographic guidance in pediatric regional anesthesia. Part 2:
Techniques. Pediatr Anesth. 2006;16:1112-24.
10. Marhofer P, Sitzwohl C, Greher M, et al. Ultrasound guidance for infraclavicular
brachial plexus anaethesia in children. Anaesthesia. 2004;59:642-6.
11. Rapp H, Grau T. Ultrasound-guided regional anesthesia in pediatric patients. Reg
Anesth Pain Manag. 2004;8:179-98.
12. Marhofer P. Upper extremity peripheral blocks. Reg Anesth Pain Manag. 2007;
11:215-21.
13. Mariano ER, Ilfeld BM, Cheng GS, et al. Feasibility of ultrasound-guided peripheral
nerve block catheters for pain control on pediatric medical missions in developing
countries. Paediatr Anaesth. 2008;18:598-601.
14. Suresh S, Chan VW. Ultrasound guided transversus abdominis plane block in infants,
children and adolescents: a simple procedural guidance for their performance.
Paediatr Anaesth. 2009;19(1):296-9.
15. Long JB, Birmingham PK, De Oliveira GS, et al. Transversus abdominis plane block in
children: a multicenter safety analysis of 1994 cases from the PRAN (pediatric regional
anesthesia network) database. Anesth Analg. 2014;119:397-9.
16. McDonnell JG, O’Donnell B, Curley G, Heffernan A, Power C, Laffey JG. The analgesic
efficacy of transversus abdominis plane block after abdominal surgery: a prospective
randomized controlled trial. Anesth Analg. 2007;104(1):193-7.
17. Pak T, Mickelson J, Yerkes E, et al. Transverse abdominis plane block: a new approach
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Paediatr Anaesth. 2009;19(1):54-6.
18. Taylor L, Birmingham P, Yerkes E, et al. Children with spinal dysraphism: transversus
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minimum effective anaesthetic volume required to block the femoral nerve. Br J
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and femoral nerve blocks in children. Br J Anaesth. 2007;98(6):797-801.
29. Walker BJ, Long JB, De Oliveira GS, Szmuk P, Setiawan C, Polaner DM, et al. The
PRAN investigators. Peripheral nerve catheters in children: an analysis of safety and
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sciatic nerve blocks with stimulating catheters for postoperative pain relief after
bilateral lower limb amputations. Anaesthesia. 2006;61:1204-7.
32. van Geffen GJ, Gielen M. Ultrasound-guided subgluteal sciatic nerve blocks with
stimulating catheters in children: A descriptive study. Anesth Analg. 2006;103:328-33.
33. Tsui BC, Ozelsel TJ. Ultrasound-guided anterior sciatic nerve block using a longitudinal
approach: “Expanding the view.” Reg Anesth Pain Med. 2008;33:275-6.
34. Schwemmer U, Markus CK, Greim CA, Brederlau J, Trautner H, Roewer N. Sonographic
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CHAPTER 4
Pain in Children: Assessment and
Management Strategies
Sharmila Ahuja
INTRODUCTION
With better understanding of mechanism of pain transmission and improved
knowledge of pharmacokinetics and dynamics, management of pain in children
has made appreciable advances in recent years. Poorly controlled postoperative
pain can result in adverse physiological responses such as neuroendocrine stress
response and hemodynamic changes, and chronic effects like longer recovery
time, psychological trauma and development of chronic pain. For these reasons,
the concept of postoperative pain, its assessment and provision of pain relief has
become an integral component of pediatric anesthesiology practice today.1
Chronic pain in children is not very well recognized and centers for diagnosis
and management of chronic pain are slow to develop.
Despite all advancements in this field, pain in children remains undertreated.
The reasons and barriers to treatment of pain in children include:
• Lack of knowledge for assessment of pain and methods of pain relief.
• Fear of adverse effects of analgesic agents such as respiratory depression,
nausea and vomiting.
• Reluctance to address the problem of pain in children, as it is considered time
consuming, involves additional effort and a proper set-up and training to deal
with pediatric pain.
This article will be addressing assessment of pain in children, management
strategies of postoperative pain and procedure-related pain.
ASSESSMENT OF PAIN IN CHILDREN

Assessment of pain in children and neonates has been a major dilemma for
clinicians. However, a reliable method for assessing pain in children is necessarily
the first step in providing adequate pain relief as well as for evaluating the efficacy
of analgesic regimens. The difficulty in obtaining an accurate measurement of
pain in pediatric patients may be due to:
• Difficulty in obtaining reliable self-reports of pain experience and
interpretation of such reports.
• Limited ability to understand pain related questions and provide appropriate
verbal response due to limited vocabulary.
• Limited research on pain-related physiology and behavior in pediatric
patients.1
Despite these difficulties, measurement of pain in children has made great

advances in the last decade. Strategies for assessment of pain in children can be
broadly divided into subjective and objective categories.
• Subjective: Self reporting methods.
• Objective: Assessment by observers which includes measurement of:
– Physiological variables
– Behavior scales
– Biological markers.
Subjective Methods of Pain Assessment

Subjective or self-reported methods are cognitive measures of pain, and attempt
to evaluate the intensity and nature of pain experienced by the child. These
methods are adaptation of techniques already established in adults and have
been shown to be better suited for the older child (>5 year of age), although some
innovative modifications have led to their successful use in children as young as
3 years of age. These include:
• Modified visual analog scale
• Color graded scale
• Self-reporting with words.
Visual Analog Scale

A 10 cm line marked “no pain” at one end and “worst possible pain” at the
other end is widely used in adults. Its applicability and reliability studied in
children showed that 50% children between ages 3 and 7 years had no difficulty
in understanding the concept of visual analog scale (VAS), other studies have
demonstrated a clear relationship between VAS and objectively assessed behavior
as indicator for pain.2 Attempts to simplify the “scale” method of subjective pain
assessment in children have been used and are reported to have lowered the
minimum age at which it could be used. A modified scale with happy/sad facial
drawings combined with a verbal or observer (nurse) scoring system has been
used by many workers in children as young as 3 years (Fig. 4.1).3
Fig. 4.1: Modified visual analog scale

Pain in Children: Assessment and Management Strategies 43
Color Graded Scale

In this, children depict their pain by coloring in a body outline using different
colored crayons to grade pain from “no hurt” to “worst pain”. It has been shown
that red (closely followed by black) is the color most frequently used by children
to describe their pain.4
Verbal Scale (Self Reporting with Words)

This is a simple scale designed for use in children where a word graphic rating
is used. In this, the child indicates “how much pain” on a line with five verbal
anchors.5
Objective Methods of Pain Assessment

Objective methods of pain assessment are suitable for the infant, neonate and
preschool child, and include:
• Behavioral measures of pain
• Measurement of physiological variables, and
• Biological markers.
Behavioral Measures
Behavior measures of pain assessment mainly fall into three main areas:
vocalization, facial expression and body movement. Behavioral pain scales
comprising of these three criteria have been used successfully by various
workers for assessment and management of acute postoperative as well as
cancer pain in children 6 months to 6 years of age. Further, these workers have
shown that the behavioral scales have good correlation with nurse observer
rated VAS scores.6
Analysis of vocalization: Crying has face validity as a measure of pain in infancy
and has been regarded as the best dependent variable for the study of pain in
infants. The simplest measure of cry is its duration. Tape recorded measurements
as well as video recorders have been used for this purpose. However, due to other
factors influencing “cry” and inter-observer variability, ‘cry’ cannot be used as a
single objective measure of pain.7
Facial expression: Izard and coworkers8 designed an objective method for
classifying different facial expressions in neonates and infants. In neonates,
the expression associated with pain was “brows down and together, nasal root
broadened and bulged, eyes tightly closed and the mouth angular and square”.
This was validated by other workers. Grunan et al.9 in a study involving neonates,
undergoing heel lance identified nine specific facial movements. Of these, brow
bulge, eye squeeze, nasolabial furrow and lip parting were documented in 96–98%
neonates.
Body movements (Motor responses): Reflex withdrawal of limb was found to be
the most common response to heel lance in neonates. However, it is important
to remember that newborns respond to any stimulus by a generalized body
movement and this is altered by different behavioral states.
Behavioral Scales
A combination of vocalization, facial expression and body movement has been
used by various workers to formulate objective pain rating scales for assessment
of pain in infants and toddlers.
• The Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS)10 rates 6
behaviors—crying, facial expression, verbal expression, torso position, touch
and leg position. This scale was used originally to assess postoperative pain,
and has been validated by many workers in children, as young as 1 year of age.
Postoperative Pain Scale by Attia et al.11 (Table 4.1) consists of 10 behavioral
indices and has been used successfully by the author for assessment of
postoperative pain in children 6 months and above undergoing cleft lip surgery.12
• The Pediatric Objective Pain Scale by Norden13 consists of five indices—arterial
blood pressure, crying, movement, agitation and posture. This scale has
been validated by several workers for assessing postoperative pain following
herniotomy, orchidopexy and circumcision.
• AIIMS Pain Discomfort Score14 also known as the ‘AIIMS Pain Scale’ is a
comprehensive scale using both subjective and objective criteria. It combines
Table 4.1 Pain assessment score11

P 0 (Poor) 1 (Mediocre) 2 (Satisfactory)
PS 1 Sleeping during None Short naps, Longer naps 10
preceding hours between 5 and 10 minutes
minutes
PS 2 Facial expression of Marked, constant Less marked, Calm, relaxed
pain intermittent
PS 3 Quality of cry Screaming, painful Modulated, can be No cry sound
high pitched distracted
PS 4 Spontaneous motor Thrashing around Moderate agitation Normal
activity agitated
PS 5 Spontaneous Tremulous, clonic Excessive reactivity Quiet
excitability and movements to any stimulation
response to ambient
stimulation
PS 6 Constant and Very pronounced Less marked Absent
excessive flexion of marked and intermittent
fingers and toes constant
PS 7 Sucking Absent/ Intermittent and Strong rhythmic
disorganized stops with crying with pacifying
sucking effect
PS 8 Global evaluation Strong Moderate Normal
hypertonicity
PS 9 Consolability None after 2 min Quiet after 1 minute Consoled before
of effort 1 minute
PS 10 Sociability (eye Absent Difficult to obtain Easy and
contact, response to prolonged
voice, smile)
Cumulative scores
20 = Comfortable
15–19 = Satisfactory analgesia
0–14 = Unsatisfactory analgesia
Table 4.2 AIIMS pain discomfort score is a comprehensive scale using both objective and
subjective criteria
Parameter Criteria Grading
Respiratory rate <+20% of preoperative baseline value 0
+20–50% of preoperative baseline value 1
>50% of preoperative baseline value 2
Heart rate +10% of preoperative baseline 0
+20% of preoperative baseline 1
+30% of preoperative baseline 2
Discomfort Calm 0
Restless 1
Agitated 2
Crying Not crying, responding to water/food and parental presence 0
Crying but responding to tender loving care 1
Crying and not responding to tender loving care 2
Pain at site of No pain 0
operation Vague 1
Can localize pain 2
Maximum score = 10
0–3 = Mild pain
4–6 = Moderate pain
7–10 = Severe pain
physiological and behavioral parameters and has been found very useful in
assessing pain in the preschool age group (Table 4.2).
Measurement of Physiological Variables

Changes in heart rate, blood pressure, ventilation rates are used widely in
conjunction with behavior scales for assessment of pain in neonates and
children.14 In newborns undergoing heel lancing or circumcision, heart rate and
blood pressure were markedly increased during and after the procedure. These
changes were found to decrease when pain relief was provided in the form of
local anesthesia.15
Fall in transcutaneous oxygen levels have been found in neonates and younger
children during painful surgical procedures such as circumcision and such
changes were found to be preventable by providing local analgesia.16
Palmar sweating has been validated as a reliable physiological measure of
the emotional state of term neonates. Marked changes in palmar sweating have
been observed during heel lance in term neonates.17 In older children, palmar
sweating index has been used to measure degree of distress during painful
surgical or dental procedures.
Biological Markers
Anand et al. carried out detailed hormonal and metabolic studies in premature
and full-term neonates undergoing surgery under regional anesthesia.18 They
documented marked release of catecholamines, glucagon, cortisol and other
corticosteroids along with suppression of insulin secretion. This resulted in
breakdown of carbohydrate and fat stores causing prolonged hyperglycemia
and increased levels of lactate, piruvate and ketone bodies.19 These stress
responses were decreased by halothane anesthesia in term neonates undergoing
painful procedures and abolished by fentanyl anesthesia20 in preterm neonates
undergoing ligation of patent ductus arteriosus. Further, these neonates had
fewer complications in the postoperative period. Similar changes have also
been documented in older infants and children undergoing various surgical
procedures.
In conclusion, it is evident that there is no single gold standard to measure
pain in children. A combination of cognitive (Self reporting), behavioral and
physiological changes are used by clinicians for assessing pain efficacy of
analgesic regimens in pediatric patients.
MANAGEMENT STRATEGIES FOR

POSTOPERATIVE PAIN IN CHILDREN
Strategies for postoperative pain control in children vary according to the age of
the child, severity of pain, type of surgery and above all the facilities available for
providing and monitoring the efficacy and side effects of the analgesic regime/
method used. Psychological considerations play a very important role in reducing
the distress of the child in pain. Comforting, holding, cuddling, use of dummies
can be used by parents/nurses or caregivers to pacify the child.21,22 For younger
children, activities such as drawing and puppet play have been used successfully
to divert the attention of the child. Establishing an Acute Pain Service goes a long
way in providing safe and reliable analgesia in children. The success of an acute
pain service for children has been proven at established centers such as Great
Ormond Street Hospital23 London and has revolutionized the postoperative pain
management in children. The requisites for establishing an acute pain service are:
• Developing protocols to suit local needs
• Must address patient medication, pain assessment and patient observations
during analgesic medication
• Dedicated consultants and clinical nurse specialists.
Minor Surgery
In most institutions around the world, a minor surgical procedure although
performed under general anesthesia, is done on day care basis. Providing
satisfactory analgesia with minimal side effects is a major consideration for day
care surgery.24 Opiates are generally avoided in day care surgery due to their
undesirable side effects such as nausea, vomiting, delayed respiratory depression,
all of which may delay the discharge of the child.
The use of local anesthetic techniques such as peripheral nerve blocks, plexus
blocks, central neuraxis blocks with a long-acting agent (bupivacaine) provides
excellent pain relief with minimal side effects. The blocks are generally performed
after induction of general anesthesia by an experienced anesthesiologist, the dose
varying according to weight of the child and type of block. The common blocks
performed for various surgical procedures and suggested dosages of bupivacaine
for these blocks are enumerated in Table 4.3.25
Table 4.3 Common nerve blocks

Block Volume of Nerve Surgical procedure
bupivacaine
(0.25)%
Axillary 0.5 mL/kg Brachial plexus Arm and hand surgery
Axillary 0.6 mL/kg Intercostal nerves Thoracotomy laparotomy
Inguinal 0.2 mL/kg Ileoinguinal, Herinotomy, orchidopexy
ileohypogastric
Penile 0.1 mL/kg Dorsal nerve of penis Circumcision
Femoral/3 in 1 block 0.5 mL/kg Femoral nerve Surgery on thigh
Caudal extradural 0.5–1 mL/kg Extradural Herniotomy, orchidopexy,
circumcision, hypospadias
Source: Adapted from Lloyd Thomas–Clinical Pediatrics. 25
Care must be taken to ensure that subsequent analgesia is provided before

the effect of the block wears off. This can be done effectively by supplementing
with simple analgesics like paracetamol, 10–15 mg/kg 6 hourly or nonsteroidal
anti-inflammatory drugs (NSAIDs) such as ibuprofen, 2.5–5 mg/kg 8 hourly and
diclofenac, 1–1.5 mg/kg 12 hourly. These analgesic drugs can be given either
orally or as suppositories, while the child is under general anesthesia.
Important considerations to be taken into account are:
• Parental consent must be taken before using suppositories
• Dosage must be adjusted when used by this route (paracetamol 20-25 mg kg/6
hours)
• NSAIDs should be avoided in neonates
Diclofenac is not recommended in infants less than six months of age.
Major Surgery
With increasing knowledge and experience in use of regional anesthesia
techniques in children, pediatric pain management has undergone a major
revolution in the past few years. These techniques range from local infiltration
and peripheral nerve blocks to field blocks, caudal and lumbar extradural blocks.
The local anesthetic agent of choice is bupivacaine because of its efficacy and
long duration of action. Toxicity has been reported with bupivacaine and the
recommended maximum safe dose of 2 mg/kg in a 4-hour-period must never
be exceeded. Caudal epidural block requires special mention, as it is a widely
used regional technique in children. The single injection ‘caudal’ has an
excellent efficacy and safety record.25 Use of adjuvants with local anesthetic
agents minimizes side effects while providing excellent pain relief. Opiates
are not preferred due to the undesirable side effects like nausea, vomiting and
respiratory depression. Ketamine (0.25 mg/kg)26 and midazolam (50 µg/kg)27
have been reported to prolong the duration of analgesia when used as adjuvants.
By using the caudal approach to the epidural space, it is possible to extend the
block to cover dermatomes as high as T10. When a more extensive block is
required, a catheter can be fed upwards to the desired level. This is possible in
infants and neonates as the epidural space is less densely packed with fat thereby
allowing the catheter to be inserted from the sacrococcygeal area to the thoracic
and lumbar region.23 In older children, lumbar epidural block provides excellent
pain relief following major surgery. Continuous infusion using mixture of local
anesthetics and opiates is used successfully in specialized units. Because of the
complexity of the technique, technical problems, risk of respiratory depression
and other undesirable side effects such as urinary retention, this technique
should be limited to those centers where facilities for continuous monitoring,
supervision and expertise is available.
Systemic Analgesia with Opioids

Continuous intravenous infusion with morphine and fentanyl is used
successfully in dedicated centers. However, this technique has certain problems
in that continuous supervision by trained personnel is a must. Besides standard
monitoring, observations for frequent pain assessment, sedation score,
respiratory rate, volume infused and other side effects such as nausea, vomiting
must be followed strictly for safe and effective use of continuous intravenous
analgesia with opiates. Patient controlled analgesia through PCA pumps can
be used effectively in children as young as 4 years. In younger children nurse
controlled analgesia (NCA) can be used where bolus doses are given by nursing
staff over and above a continuous background infusion after assessing level of
discomfort or before procedures known to cause discomfort, such as changing
position or physiotherapy.25
Important considerations for PCA/NCA are:
• Availability of trained personnel
• Continuous monitoring for sedation, respiratory depression, nausea vomiting
essential
• Antiemetics for prevention and treatment of nausea vomiting must be included
in protocol
• Must be tailored to the individual patient.
Use of Non-narcotic Analgesics

Nonsteroidal anti-inflammatory agents (NSAIDs) are widely used for treatment
of mild to moderate pain in children. These agents are particularly useful for
supplementation of analgesia with regional/local anesthesia techniques.
Agents used commonly in children are:
Paracetamol, used orally or rectally in a dose of 10–15 mg/kg, maximum dose
should not exceed 60 mg/kg/day. IV dose should be given according to post-
gestational age, 28–32 weeks 10 mg/kg, 32–36 weeks 12.5 mg/kg and ≥36 weeks
15 mg/kg.
Ibuprofen in dosage of 5–10 mg/kg, maximum dose 40 mg/kg/day
Diclofenac in dosage of 1–2 mg/kg; maximum daily dose 3 mg/kg. Diclofenac
is available as suppositories in strengths of 12.5 mg, 25 mg, 50 mg and 100 mg.
However, suppositories are not recommended for children less than 12 months
old.
Ibuprofen and diclofenac are not recommended in infants less than 12 months
of age and one must lookout for gastrointestinal, hematological and renal side
effects whenever these agents are used.22
Role of Parent and Patient Information

Prior information and discussion about the various analgesic techniques with
parents play a vital role in pain management in children. Information given via
audiovisual aids and pamphlets should include need to treat pain and the various
methods of managing pain. Preoperative patient education and preparation
helps to reduce anxiety and has been seen to reduce postoperative pain.24
Procedure Related Pain

Certain medical procedures (both therapeutic and diagnostic) that are performed
on children may be unpleasant or painful and cause a lot of distress and anxiety
to the child as also to the parents. This may then result in a child fearful of
undergoing future procedures and a lifetime of unpleasant memories.
These procedures include venous cannulation, cleaning of a wound, removal
of sutures and more invasive interventions like lumbar puncture. The approach
to management of procedural pain includes the following:
• Adequate explanation of the procedure to the parent and to the child (who can
understand) in simple understandable language.
• Parental support and presence should be encouraged.
• Procedure should be performed in a safe clean area away from bedside if
possible, to minimize contamination and development of fear of ‘bedside’.
• All equipments required for the procedure should be prepared in advance to
reduce any delay in performing the procedure.
Depending on procedure, a combination of psychological and pharmacological
techniques may be used.28 Simple procedures may be performed by using
distraction method and play along with local anesthetic creams.
If the procedure is a painful one, analgesia should be provided before
performing the procedure. Oral/rectal paracetamol in appropriate dosages
(Table 4.4) along with soothing and cuddling may suffice for minor less painful
procedures. Newer drugs such as dexmedetomidine is being used successfully
for sedoanalgesia techniques during some radiological procedures. Intranasal
dexmedetomidine in a premedication dose of 2 µg/kg has resulted in excellent
sedation in children without causing adverse hemodynamic effects.29
Table 4.4 Dosing schedule for minor analgesics

Drug Dose (mg/kg) Dose interval (hrs)
Paracetamol
Oral Antipyretic 10 6
Analgesic 15–20
Rectal Antipyretic 15 6
Analgesic 20–25
Intravenous 10–15 (based on post- 8
gestational age)
Ibuprofen Oral 5 6
Diclofenac Oral 1 8–12
Rectal 1 8–12
Ketorolac Intravenous 0.2–0.5 (from 1 yr) 6 (max 8 doses)
Table 4.5 Suggested doses of patient controlled anesthesia (PCA)/nurse controlled

anesthesia (NCA)
Morphine PCA Day of operation Thereafter NCA
Loading dose (µg/kg) 50–100 50–100 50–100 50–100
Background infusion (µg/kg) 0–2 4–8 0–4 10–20
Bolus dose (µg/kg) 10–20 10–20 10–20 10–20
Lockout interval (mins) 5–10 10–20 5–10 30
4 hours dose limit (µg/kg) 400 400 400 400
Source: Lloyd Thomas, et al. Hospital for sick children, great ormond street, London, UK
If drugs are given for sedation, facility for monitoring and resuscitation must
be present. These include availability of source of oxygen, suction apparatus
and emergency resuscitative drugs. Presence of an anesthesiologist is desirable
whenever the child requires deeper level of sedation.
Nonpharmacological methods for facilitating performance of procedures in
children have been used successfully by pediatric care givers. These include:
• Distraction tactics such as music, play, storytelling, etc.
• Relaxation techniques may be tried in older children by prior suggestion and
use of breathing exercises.
• Guided imagery use of distraction and relaxation by trained personnel
whereby the child is guided through sensory image which has produced a
pleasant sensation in the past.
• Massage: This may be performed by the parent or a trained friendly person. It
involves gentle massage of soft tissues to produce a sense of wellbeing.28
FUTURE PERSPECTIVES IN PAIN MANAGEMENT

Day care surgery has presented a new set of challenges and goals for the
anesthesiologist. Newer innovations in pain management include target
infusion techniques, patient controlled regional anesthesia (PCRA) systems,
newer drug delivery system such as transdermal iontophoresis, transmucosal
or intranasal delivery of drugs and further advances in opioid therapy. The final
aim, needless to say, is to ‘provide effective analgesia with minimal side effects’
(Table 4.5).
CONCLUSION
It is imperative for care givers involved in management of pediatric pain to
expand and update knowledge in the field, use appropriate tools and techniques
for assessment and intervention by adopting a multimodal and multidisciplinary
approach, and above all, involve parents and family in the entire process of pain
management.
KEY POINTS
• C hildren feel as much pain as adults following tissue injury, trauma, operative
procedures and simple medical procedures (procedure related pain).
• Assessment of pain in children is an important step in providing/initiating pain relief
and evaluating efficacy of analgesic regimes.
• Pain in children may be assessed by ‘subjective’ or self-reporting methods and ‘objective’
pain scales which include physiological variables, behavior scales and biological
markers.
• Strategies for pain control in children vary according to age, type and severity of pain,
type of surgery and facilities available for providing pain relief and monitoring thereof.
• Establishing ‘Acute Pain Service’ goes a long way in providing safe and reliable analgesia
in children.
• Providing satisfactory analgesia with minimal side effects is the mainstay of pain
management for day care or minor surgical procedures.
• Regional anesthesia techniques, peripheral nerve blocks, plexus blocks, neuraxis
blocks (ranging from caudal to lumbar extradural blocks) provide excellent pain relief.
Systemic analgesia with opioids in dedicated centers provides good pain relief in the
form of PCA and NCA.
• Procedure related pain from venous cannulation, wound dressing, suture
removal, lumbar puncture cause distress and discomfort to child and parents.
Nonpharmacological methods such as distraction tactics, cuddling and soothing along
with LA creams suffice for simple procedures.
• Pharmacological approach with analgesics and sedatives may be required for more
painful procedures. Paracetamol is the most common agent used by oral/rectal route.
• Use of sedative agents demand monitoring and resuscitative facilities. Agents for
sedation include midazolam and more recently dexmedetomidine given under
supervision only in calculated dosages.
REFERENCES
1. Charles BB, Anand KS, Sethna N. Pediatric pain management. In: Textbook of
Paediatric Anaesthesia. Groege A Gregory (ed). 1989;2:687-93.
2. Maunuksela EL, Olkkola KT, Korpela R. Measurement of pain in children with self-
reporting and behavioral assessment. Clin Pharmacol Ther. 1987;42(2):137-41.
3. Rawal N. Analgesia for day-care surgery. Br J Anaesth. 2001;87:73-87.
4. Eland JM, Andersen JE. The experience of pain in children. In: Pain: A source book for
nurses and other health professionals. Jacox AK (ed.) Little Brown, Boston, 1977.
5. Tesler MD, Sevedra MC, Holzemer WL, Wilkie DJ, Ward JA, Paul SM. The word-graphic
rating scale as measure of children’s and adolesents’ pain intensity. Res Nurs Health.
1991;14(5):361-71.
6. Voepel-Lewis T, Merkel S, Tait AR, Trzcinka A, Malviya S. The reliability and validity
of the face, legs, activity, cry, consolability observational tool as a measure of pain in
children with cognitive impairment. Anesth Analg. 2002;95(5):1224-9.
7. Michelsson K, Reas J, Thoden CJ, et al. Sound spectrographic cry analysis in neonatal
diagnostics: an evaluation study. J Phonet. 1982;10:79.
8. Izard CE, Huebner RR, Risser D. The young infants ability to produce discrete emotional
expressions. Dev Psychol. 1980;16:132.
9. Grunan RVE, Craig KD. Pain expression in neonates: facial action and cry. Pain. 1987;
28(3):395-410.
10. McGrath PJ, Johnson G, Goodman J, et al. The Children’s Hospital of Eastern Ontario
Pain Scale (CHEOPS). In: Advances in pain research and therapy. Fields H, Dubner R,
Cervero F (eds.) Raven Press, New York; 1984.pp.395-402.
11. Attia J, Amiel-Tison C, Mayer MN, et al. Measurement of postoperative pain and
narcotic administration in infants using a new clinical scoring system. Anaesthesiol.
1987;16:A532.
12. Ahuja S, Datta A, Krishna A, Bhattacharya A. Infra-orbital nerve block for relief of
postoperative pain following cleft lip surgery in infants. Anaesthesia. 1994;49:441-4.
13. NordenJ, Hannallah R, Geston P, et al. Concurrent validation of an objective pain scale
for infants and children. Anaesthesiol. 1991;75:A934.
14. Pawar DK, Robinson S, Brown TCK. Pain management in anaesthesia for children.
Brown TCK, Fisk GC (eds). Blackwell Scientific Publications. New York; 1992.pp.127-37.
15. Owen ME, Todd ED. Pain in infancy, neonatal reaction to heel lance. Pain. 1984;20:77.
16. Williamson PS, Williamson ML. Physiological stress reduction by a local anaesthetic
during newborn circumcision. Paediatrics. 1983;71:36.
17. Harpin VA, Rutter N. Development of emotional sweating in the newborn infant. Arch
Dis Child. 1983;58:226.
18. Anand KJS. Hormonal and metabolic functions of neonates and infants undergoing
surgery. Curr Opin Cardiol. 1986;1:681.
19. Anand KJS, Ansley-Green A. Does the newborn infant require anaesthesia during
surgery? Answer from a randomized trial of halothane anaesthesia. Pain Res Clin
Management. 1988;3:329.
20. Anand KJS, Sipell WG. Aynsley-Green A. A randomized trial of fentanyl anaesthesia
in preterm neonates undergoing surgery: effects on the stress response. Lancet.
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21. Frank LS. A national survey of the assessment and treatment of pain and agitation in
the neonatal intensive care unit. J Obstet Gynecol Neonat Nurs. 1987;16:387-93.
22. Kumar A, Bhattacharya A, Agarwal M. Paediatric pain: perception, assessment and
management. J Anaesth Clin Pharmacol. 1997;13:99-111.
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1993;3:234-7.
24. Rawal N. Analgesia for day care surgery. Br J Ananesth. 2001;87:73-87.
25. Lloyd Thomas AR, Howard RF, Llewellyn N. The management of acute pain and
postoperative pain in infancy and childhood. In Clin Pediatrics. 1995;3(3):579-98.
26. Weber F, Wolf H. Caudal bupivacaine and S+ ketamine for postoperative analgesia in
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bupivacaine. Can J Anaesth. 1995;42(9):758-64.
28. Mary Cunliff, Stephen A Roberts. Pain management in children. Current Anaesthesia &
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dexmedetomidine doses for premedication in children. Anaesthesia. 2012;11:1210-6.
CHAPTER 5
Severity of Illness Scoring Systems
and Their Clinical Relevance
BK Rao
INTRODUCTION
Intensive care is a complex system of healthcare delivery which is carried out
in a very heterogeneous patient population, by varied set of physicians, and in
different resource, infrastructural and cultural settings. Though there is lack of
conclusive scientific evidence indicating what treatments and practices are
optimal, the increasing cost of ICU care demands evidence of effectiveness and
efficiency of ICU practices. For any meaningful comparisons, the ICU data need
to be risk stratified using scoring systems.
This chapter will give an overview of the commonly used severity Scoring
systems such as Acute Physiology and Chronic Health Evaluation (APACHE),
Simplified Acute Physiology Score (SAPS) and Mortality Probability Model
(MPM) and Organ dysfunction systems such as Sequential Organ Failure
Assessment (SOFA), Multiple Organ Dysfunction Score (MODS) and Logistic
Organ Dysfunction Score (LODS).
BRIEF HISTORY
Many attempts to create scoring systems in medicine were made in the last several
decades. The first ICU model of disease severity, the Therapeutic Intervention
Scoring System (TISS), was introduced in 1974. Based on the assumption that
it is possible to assess the severity of acute illness by quantifying the degree of
physiologic parameters abnormality, Acute Physiology and Chronic Health
Evaluation (APACHE) was developed in the George Washington University
Medical Center in 1981,1 followed by the introduction of the Simplified Acute
Physiology Score (SAPS) and Mortality Probability Model (MPM).2,3 APACHE
system was later updated to APACHE II.4 Within a decade of their introduction,
the scoring systems were able to do severity of illness assessment, mortality
predictions and classify ICU patients based on risk stratification.
Around the same time, concerns were raised about errors in their prediction
caused by their use outside the reference data, which was used for the original
model development and validation, changing patient demographics and disease
profile, ICU care practices, and availability of newer technology, diagnostic and
therapeutic agents. This led to the development of the scoring systems subsequent
versions APACHE III,5 the SAPS II6 and the MPM II7 between 1991 and 1993, and
later to SAPS 3,8,9 APACHE IV10 and MPM III11 between 2005 and 2007 (Table 5.1).
Table 5.1 General predictive scoring systems

1st generation 2nd generation 3rd generation 4th generation
APACHE I1 APACHE II4 APACHE III5 APACHE IV10
SAPS I2 SAPS II6 SAPS III8,9
MPM I3 MPM II7 MPM III11
Abbreviations: APACHE, acute physiology and chronic health evaluation; SAPS, simplified acute physiology
score; MPM, mortality probability model
To evaluate the organ function performance level during stay in ICU, organ
dysfunction scores like Sequential Organ Failure Assessment (SOFA) score,12
Multiple Organ Dysfunction Score (MODS),13 and Logistic Organ Dysfunction
Score (LODS) score14 were developed between 1994 and 1996. In between
many other severity scores were developed but none has gained the popularity
matching the general physiology-based systems. General scoring systems have
been developed, widely used and validated in mixed ICU population, but are not
validated for specific patient groups such as trauma, burns and cardiac surgery.
DEVELOPMENT OF SCORING MODEL

Severity of illness is generally assessed using a variety of demographic, clinical,
physiological, and laboratory variables. Severity of illness score comprise two
parts: acute physiology score (APS) to assess the degree of acute illness and
preexisting chronic health status of the patient; and the probability model which
uses coefficients and equations to give the probability of hospital death of the
patient.
Development of the prediction model is a multistep process requiring
important predictors’ identification and their weighted contribution in the score,
and use of discrimination and calibration to assess the performance of the model,
followed by its validation. Discrimination distinguishes between patients who
will die from patients who will survive and is measured using the area under the
receiving operating characteristic curve. AUC ROC (area under curve, receiver
operating characteristic) above 0.8 is desirable for a good model. Calibration is
a measure of the observed mortality in relation to the expected mortality, and
is sensitive to alterations in case-mix and patient care/interventions. Calibration
and discrimination in the analyzed population is evaluated by the goodness
of fit.15,16 An ideal model need to be well-calibrated and discriminated and
validated. Whenever any model’s accuracy deteriorates, the model needs to be
customized or revised and updated.
The most influential predictors were initially determined and weighted
by consensus panel of experts (first version of APACHE in 1981, first version of
SAPS in 1984, and APACHE II in 1985); all other models of APACHE, SAP, MPM
were developed using logistic regression techniques. Statistical techniques
such as artificial neural networks and genetic algorithms were also used to
develop models which are now largely used in academics. Organ failure scores
are sequential scores which measure the number and/or the intensity of organ
dysfunction. By contrast with the SAPS, MPM, and APACHE scores, they do not
take age, category of admission, or underlying diseases into account, because
these items do not change over the ICU stay.
Severity of Illness Scoring Systems and Their Clinical Relevance 55
The severity scoring models’ development clearly followed two approaches:

simplicity of model for easy use vs complexity of model to ensure performance
accuracy; free vs paid models. APACHE II, SAPS and MPM maintains simplicity
and are free; APACHE III and IV are complex; the models, software, and services
are proprietary.
SEVERITY OF ILLNESS MODELS

Severity of illness scoring systems either assess disease severity at the time of
ICU admission and use it for outcome prediction (e.g. APACHE, SAPS, MPM); or
assess the presence and severity of organ dysfunction on admission and during
the ICU stay (e.g. SOFA, MODS).
Acute Physiology and Chronic Health Evaluation

APACHE has four versions or generations I to IV.
First Generation–APACHE I
APACHE I was published in 1981.1 APACHE I, consisting of 34 physiologic variables
and preadmission health status, was considered too complex for manual use.
Second Generation–APACHE II
APACHE II was developed and validated on data of 5815 medical and surgical
ICU patients at 13 US tertiary care centers between 1979 and 1982. APACHE II
was introduced in clinical practice in 1985 with a reduced number of predictive
physiological variables from 34 to 12, age, previous health status, and ICU
admission diagnosis.4
The physiological parameters were heart rate, mean arterial blood pressure,
temperature, respiratory rate, alveolar to arterial oxygen tension gradient,
hematocrit, white blood cell count, creatinine, sodium, potassium, pH/
bicarbonate, and Glasgow Coma Scale (GCS) score. Physiological data for
calculation of the APACHE II score are derived from the worst values in the first
24 hours after admission to the ICU, the total APACHE II scores range from 0 to
71. APACHE II is the most widely used illness scoring system in the world but has
concerns pertaining to patient selection and hospital stay before ICU admission
(Table 5.2).
Third Generation–APACHE III

APACHE III, developed in 1991, is similar in concept to APACHE II. Besides having
expanded number of ICU admission diagnoses and physiological variables,
remodeled coefficients, equations for daily prediction of individual outcomes,
APACHE III also has new parameters of adjustments for location and duration
of stay before ICU admission, newer equations to predict LOS, active therapy risk
and mechanical ventilation duration, which were missing in APACHE II.5
After an initial independent validation between 1993 and 1996, the subsequent
validation from 1998 to 2002 required two updated versions (APACHE III-I, J).17
These too showed good discrimination but poor calibration when used in intensive
care units outside USA, where it was originally developed.18
56
Table 5.2 Acute physiology and chronic health evaluation (APACHE)-II4
Physiologic variables High abnormal range Normal range Low abnormal range
+4 +3 +2 +1 0 +1 +2 +3 +4
Temperature-Rectal (⁰C) ≥ 41 39–40.9 38.5–38.9 36–38.4 34–35.9 32–33.9 30–31.9 < 29.9
MAP (mm Hg) ≥ 160 130–159 110–129 70–109 50–69 < 49
HR (ventricular response) ≥ 180 140–179 110–139 70–109 55–69 40–54 < 39
Respiratory rate (non-ventilated or ventilated) ≥ 50 35–49 25–34 12–24 10–11 6–9 <5
Oxygenation: A-aDO2 or PaO2 (mm Hg) ≥ 500 350–499 200–349 < 200
FiO2 > 0.5 record A-aDO2

FiO2 < 0.5 record PaO2 PO2 >70 PO2 61–70 PO255–60 PO2 < 55
Arterial pH ≥ 7.7 7.6–7.69 7.5–7.59 7.33–7.49 7.25–7.32 7.15–7.24 <7.15
Serum HCO3 (venous mEq/L) (not preferred, ≥ 52 41–51.9 32–40.9 22–31.9 18–21.9 15–17.9 <15
but may use if no ABGs)
Serum sodium (mEq/L) ≥ 180 160–179 155–159 150–154 130–149 120–129 111–119 ≤ 110
Serum potassium (mEq/L) ≥7 6–6.9 5.5–5.9 3.5–5.4 3–3.4 2.5–2.9 < 2.5
Serum creatinine (mg/dL) ≥ 3.5 2–3.4 1.5–1.9 0.6–1.4 < 0.6
Double point score for acute renal failure
Hematocrit (%) ≥ 60 50–59.9 46–49.9 30–45.9 20–29.9 < 20
White blood count (total/mm3) ≥ 40 20–39.9 15–19.9 3–14.9 1–2.9 <1
Glasgow coma score (GCS)
Score = 15 minus actual GCS
A. Total acute physiology score (sum of 12 above points)
B. Age points (years) ≤ 44 = 0; 45 to 54 = 2; 55 to 64 = 3; 65 to 74 = 5; ≥ 75 = 6
C. Chronic health points 2 points for elective postoperative admission
5 points if emergency operation or nonoperative admission, if patient has significant chronic liver, cardiovascular,
respiratory or renal disease or is immunocompromised
Total APACHE II score (add together the points from A+B+C)
Abbreviations: MAP, mean arterial pressure; A-aDO2, alveolar-arterial oxygen gradient; FiO2, fractional inspired oxygen
APACHE III logistic regression coefficients and equations are proprietary and
are available only with permission.
Fourth Generation–APACHE IV
APACHE IV model was published in 2006.10 Data were collected between 2001–
2002 from 110,558 patients from 104 intensive care or coronary care units of 45
selected hospitals across USA. APACHE IV uses 142 variables (age, chronic health
conditions, and physiologic data required to calculate an acute physiology score
[APS] of APACHE III). The worst values from the initial 24 hours of intensive care
unit admission are considered. APACHE IV also includes the patient’s location
and length of stay before ICU admission, primary diagnosis at ICU admission,
use of mechanical ventilation and if an emergency surgery was performed, PaO2/
FIO2 ratio, and whether sedation or paralysis resulted in an inability to assess GCS
score. The score ranges from 0 to 250. APACHE IV has excellent discrimination
and calibration. Its predicted mortality is more accurate than APACHE III.
APACHE IV had good predictive accuracy within the subgroup acute
myocardial infarction and CABG.10 Trials in sepsis tend to combine medical and
surgical patient populations, with multiple anatomic sites of infection, APACHE IV
was reported to be a poor predictor of mortality in the Surgical Abdominal Sepsis
(SABS) population.19
APACHE IV model provides clinically useful ICU length of stay predictions
and assessment of patient and non-patient factors that affect ICU stay. However,
its accuracy and utility are limited for individual patients.20 External validation
studies suggest superior discrimination with APACHE IV when compared with
other scoring systems.21,22 Bhattacharya and Todi found that in comparison to
APACHE IV the mortality was overestimated by APACHE II in an Indian ICU.23
The burden of data entry for APACHE IV is significant as compared with
other predictive models, the number of input variables is high, particularly when
the collection of data is manual. In a randomly selected patient population, the
average time for chart abstraction for the MPM0 III, SAPS II, and APACHE IV
models was 11, 20, and 37 minutes, respectively.21 The solution may be provided
by information technology permitting electronic record systems that can
automatically extract the relevant data.
Simplified Acute Physiologic Score

Simplified Acute Physiologic Score system (SAPS), an abbreviated simplified
version of the original APACHE score, was published in 1984.2 It was developed
from a data set of 13,152 patients from 137 adult medical and/or surgical ICUs in
12 countries. This model is a logistic regression model that uses clinical ICU data
of the first 24 hrs after ICU admission. The SAPS II includes only 17 variables:
12 physiology variables, age, type of admission (scheduled surgical, unscheduled
surgical, or medical); and three underlying disease variables (acquired
immunodeficiency syndrome, metastatic cancer, and hematologic malignancy).6
Though the reported overall discrimination of SAPS is good, an overestimation
in high-risk patient groups and a poor calibration in certain patient subgroups
have also been reported.24,25 SAPS II scores are more popular than APACHE and
MPM in many European countries. Local calibrations of SAPS II are regularly
performed all over Europe.26,27
SAPS III, published in 2005, was developed from a data base of 16,784 patients
(mostly mixed medical-surgical) from 303 ICUs in 35 countries using advanced
statistical tools.8,9 Data were collected at ICU admission (within an hour before
or after ICU admission), on days 1, 2 and 3, and on the last day of the ICU stay.
The admission data includes socio-demographic data, and other data related
to condition of the patient before ICU admission, such as chronic conditions
and medical diseases; patient’s condition at ICU admission, such as the reason
for admission, infection at admission, and surgical status; and the patient’s
physiologic derangement at ICU admission. These data were collected within an
hour before or after ICU admission. The total score range from 0 to 217. SAPS 3
also includes customized equations for prediction of hospital mortality in seven
geographical regions of the world. SAPS II was tested in the SAPS 3 Hospital
Outcome Cohort which was geographically more diverse than the reference
base used to develop SAPS II. Discrimination of SAPS II was good but hospital
mortality was underestimated as compared to SAPS 3.8,9
External validation studies in other ICU populations reported that SAPS 3
had good discrimination, but poorer calibration, especially when compared with
APACHE IV and MPM0 III, SAPS II.28-32 Although SAPS 3 does not predict the
length of stay, SAPS can compare the resource use by different ICUs using the
standardized resource use parameter based length of stay in the ICU adjusted
for severity of acute illness.33 There are many reports suggesting the need for
recalibration of SAPS III due to deteriorating calibration accuracy.29,30,32,34 A
customized eSAP III automates the risk assessment using data from electronic
medical records (EMR) and is reported to be as good as the original SAPS III.35
Mortality Prediction Model

There are three versions of the Mortality Prediction Model (MPM0 I, MPM0
II, MPM0 III). The first MPM developed in 1985 from patients in a single ICU.3
MPM II was developed in 1993 using logistic regression techniques on a large
international database of 12,610 ICU patients.7 MPM II consists of two scores:
MPM0, the admission model (hence the term “0”) and MPM24, the 24-hour model.
The 24 hour model demonstrated poor calibration and discrimination at 48 and
72. Lemeshow et al36 developed 48 hours and 72 hours model which contain the
same 13 variables and coefficients as the MPM24.
MPM0 III was developed in 2007 using 124,000 patient’s data from 135
American ICUs at 98 hospitals participating in the project IMPACT.11 It provides
an assessment of acuity based on age and 15 binary variables measured at the
time of or within 1 hour of ICU admission. A severity score is calculated from
variables and entered into a mathematical formula which gives the predicted
mortality. The MPM0 III, has good discrimination and calibration, and has been
externally validated in ICU populations from 135 ICUs in USA and Brazil.37
With the addition of new variables and interaction effects, MPM0-III provides
more accurate comparisons of actual vs. expected ICU outcomes compared to
MPM II.11 MPM systems have the lowest extraction burden among the three
major predictive scoring systems (APACHE, SAPS, MPM) since they do not use
laboratory data but rather clinical and physiologic data only.
Sequential (Sepsis-related) Organ Failure Assessment

The sequential organ failure assessment (SOFA) score was developed in 1994
during a consensus conference organized by the European Society of Intensive
Care and Emergency Medicine to quantify the severity of the patients’ illness
based on the degree of organ dysfunction over time.12 Six-organ systems were
selected: respiratory, cardiovascular, hepatic, renal, coagulation, central nervous
system. Organ functions are scored from 0 (normal function) through 4 (most
abnormal) giving a possible score of 0 to 24 and the worst value on each day is
recorded. The scores are calculated 24 hours after admission to the ICU and
every 48 hours thereafter (thus, the term “Sequential” Organ Failure Assessment)
(Table 5.3).
Total maximum SOFA score and delta SOFA can be used to quantify the
degree of dysfunction/failure already present on ICU admission, the degree of
dysfunction/failure that appears during the ICU stay and the cumulative insult
suffered by the patient. A high total SOFA score (SOFA max) and a high delta SOFA
(the total maximum SOFA minus the admission total SOFA) have been shown to
be related to a worse outcome38,39 and the total score has been shown to increase
over time in non-survivors compared to survivors.
The Society of Critical Care Medicine (SCCM) and the European Society of
Intensive Care Medicine (ESICM) have endorsed the use of SOFA for identifying
patients at risk of dying from sepsis.40-42 A qSOFA Score, a simplified version of the
SOFA score, was introduced by the Sepsis-3 group in 2016 as an initial assessment
tool to identify patients with infection who were at high risk of death.40
Multiple Organ Dysfunction Score

Multiple organ dysfunction syndrome is the leading cause of morbidity and
mortality in ICU patients. In light of the lack of consensus on the criteria used to
define the clinical syndrome, Marshal et al. analyzed clinical studies of multiple
organ failure that were published between 1969 and 1993, and identified seven
Table 5.3 Sequential organ failure assessment (SOFA)12

Organ failure Variables Score 0 Score 1 Score 2 Score 3 Score 4
Respiratory PaO2/FiO2 >400 <400 <300 <200 MV <100 MV
Renal Creatinine (mg/dL) <1.2 1.2–1.9 2.0–3.4 3.5–4.9 >5.0
Urine output (mL/day) >500 <500
Mean arterial blood >70 <70
pressure, mmHg
Cardiovascular Dopamine <5 >5 >15
Dobutamine Any dose
All doses in Epinephrine <0.1 >0.1
mcg/kg/min
Norepinephrine <0.1 >0.1
Hepatic Bilirubin mg/dL <1.2 1.2–1.9 2.0–5.9 6.0–11.9 >12.0
Hematological Platelets 109/L >150 <150 <100 <50 <20
CNS GCS 15 13–14 10–12 6–9 <6
Abbreviations: MV, mechanical ventilation; CNS, central nervous system; GCS, Glasgow coma scale
systems defined the multiple organ dysfunction syndrome. In the final model,
gastrointestinal function was dropped for want of descriptors of function. Variables
were assigned to the remaining six systems (respiratory, cardiovascular, renal,
hepatic, hematological and central nervous system). A composite variable, the
pressure-adjusted heart rate (heart rate × central venous pressure/mean arterial
pressure), was developed for cardiovascular system. First parameters of the day
are used for each of the six organs to calculate the score which ranges between
0 and 4 is awarded, giving a total maximum score of 24. The sum of individual
organ score gives the aggregate multiple organ dysfunction score (MODS). The
score was developed and validated in a single surgical ICU.13 MODS was not
designed to predict mortality, but an increasing MODS does correlate with ICU
outcome. The delta MODS reflects organ dysfunction developing during the ICU
stay and may be more predictive of outcome than individual scores.
Logistic Organ Dysfunction Score

Logistic organ dysfunction score (LODS) was developed in 1996 using a database
of 13,152 admissions to 137 adult medial surgical ICUs in 12 countries from
the European North American Study of Severity Systems.14 Twelve variables
representing the function of six organ systems (neurologic, cardiovascular, renal,
pulmonary, hematologic and hepatic) were selected. Each organ system was
assigned points for the worst value for any variable for that system in the first 24
hours of ICU admission. LOD points were assigned to the levels of severity (score
0 for no dysfunction, score 5 for maximum dysfunction) and the resulting LOD
scores ranged from 0 to 22 points.
The LODS is well-correlated with the numbers and levels of organ dysfunctions
and discriminates well between survivors and non-survivors, greater severity of
organ dysfunction was consistently associated with higher mortality.43 LODS
system is quite complex and is seldom used.
COMPARISON OF SCORING MODELS

Several studies have reported lack of generalizability of prognostic models,
requiring their validation and recalibration if they are to be used for a patient
population different from the one used to develop the models. Customization of
existing models may be an important strategy to ensure accuracy of results.
Beck et al.44 conducted an external validation of SAPS II, APACHE II and
APACHE III prognostic models in 16,646 adult intensive care patients admitted
between 1993 and 1996 in 17 ICUs in South England. The external validation
showed good discrimination, but imperfect calibration for all three models
tested. Harrison et al.24 investigated adult risk prediction models in 1,41,106
patients admitted in 63 adult general critical care units in England, Wales, and
Northern Ireland between 1995 and 2003. APACHE II, APACHE II UK, APACHE
III, SAPS II, and MPM II models showed good discrimination but poor calibration.
Recalibration of the models showed some improvement in discrimination and
calibration. Livingston and colleagues45 compared the APACHE II and III, UK
APACHE II, SAPS II, and MPM0 and MPM24 in a large number of patients admitted
in Scottish ICUs. All models showed good discrimination but poor calibration.
Best overall performance was seen with SAPS II, although APACHE II showed
better calibration.
In a large retrospective study, Kuzniewicz et al.21 calculated standardized

mortality ratios (SMRs) in 35 hospitals in California, USA, using the mortality
probability model III (MPM0 III), the SAPS II, and the APACHE IV risk- adjustment
models. The discrimination and calibration were adequate for all risk-adjustment
models. APACHE IV had the best discrimination. There was a large variation in
SMRs among the ICUs in all the models used; which could be due to differences
in model performance itself or due to some unmeasured differences in the case
mix.
Recently nearly 6000 patients from three Brazilian ICUs, the APACHE IV,
SAPS III, and MPM0 III were studied. All models showed poor calibration,
while discrimination was very good for all of them. APACHE IV showed
better discrimination than SAPS III and MPM0 III. APACHE IV showed better
discrimination than SAPS III and MPM0 III.31 In another study, Kramer et al.
found that APACHE IV had superior discrimination and calibration compared to
MPM0 III.46
Though organ dysfunction systems have not been used regularly in clinical
practice, repeated measurements of the dysfunction score can effectively provide
information about progress of dysfunction, the response to interventions made
and resource use. Various investigators have reported no significant differences
between MODS and SOFA for mortality prediction;47 better outcome prediction
compared to the MODS using the cardiovascular component for the SOFA
score;47 better discrimination of SOFA compared to MODS in patients with brain
injury.48
Large randomized trials showing superiority of one predictive system over
another are lacking. APACHE, SAPS and MPM are the most frequently used
general scoring systems for assessment of severity of illness and outcome
predictions, and SOFA is most used organ dysfunction scoring system. Generally,
APACHE IV tends to be more accurate for predicting mortality than the others.
USES OF SEVERITY-OF-ILLNESS SYSTEMS

ICU Performance and Cost of Care
Patient risk-adjusted mortality or length of stay provided by scoring systems
can be used as measures of performance assessment and improvement. Many
institutions and agencies in the world such as the Joint Commission, USA;
Netherlands’ National Intensive Care Evaluation Program; Australia and New
Zealand Intensive Care Society, and Intensive Care National Audit and Research
Centre, UK, have recommended or adopted APACHE or a simpler model with
or without length of stay for national comparison of the ICU performances for
patient groups. Earlier, the Society of Critical Care Medicine (SCCM) Project
IMPACT was an attempt to describe and measure the care of ICU patients using
MPM II, SAPS II, and APACHE II, and benchmark hospitals using MPM II.
The ratio between observed and predicted mortality called the standardized
mortality ratio (SMR) and hospital standardized mortality ratio (HSMR) are used
in some parts of the world.49 The Hospital’s mortality performance assessed by a
SMR is not much impacted by the model chosen to assess mortality.
Assessing ICU performance solely based on medical outcomes will be biased
unless resource usage is also considered alongside. However, assessment of
resource use is far less straightforward and the information relating the costs of
ICU care and resource usage for critically ill patients is limited. General scoring
systems do not reliably predict costs in critically ill patients. The cost varies
according to the severity of the patients’ disease severity and the use of costly
novel and high end therapies. Though length of stay is a significant determinant
of resource use, costs can vary because of other reasons as well49,33 and also the
ICU length of stay can vary even after accounting for patient risk factors because
of other factors.50 Also, since the distribution of ICU LOS is highly variable, it is
probably inappropriate to use APACHE II or III scores to predict or adjust LOS.51
APACHE IV is the most accurate and best calibrated model for LOS. Although it
is less accurate, MPM0 III may be a reasonable option.52 APACHE IV data from
ICU day 5 can identify patients who may have prolonged ICU stay.53 APACHE IV
models for predicting resource use account for the impact of ICU readmission
and LOS but its accuracy and utility are limited for individual patients.10
A significant proportion of patients admitted to the ICU have a low probability
of death and do not receive ICU or organ-specific interventions. Greater use of
ICU care does not always lead to better outcomes and by decreasing the ICU
admission of low-risk severity patients, the cost-effectiveness of ICU care may
be improved.54 But in some patient, populations with borderline indication for
ICU admission, like elderly with pneumonia, ICU care has reduced mortality at
no significant extra cost.55 Mortality probabilities generated by general predictive
systems APACHE II; APACHE III; SAPS II fail to accurately reflect the mortality
experienced by low mortality subgroup of ICU admissions.56 Further validation is
needed for the use of severity of illness scores for ICU admission triage in low-risk
patients.
Clinical Trials
Severity of illness and risk-adjusted mortality rates are used extensively in the
studies to draw a meaningful comparison and inference. The disease severity
scoring used for risk adjustment (also called case-mix adjustment) ensures
similar disease burden in the control and study groups, and identifies eligible
patients for inclusion in the study.
SAPS II and APACHE II are the most used models to describe illness severity
in clinical trials. The choice between existing severity scoring systems remains
largely subjective and depends on the performance in the population of interest,
feasibility, availability of resources.
Outcome prediction systems have been used to evaluate various interventions
and drug efficacy trials in sepsis, pneumonia, ARDS.57 In the PROWESS and
ADDESS Recombinant Human Activated Protein C (APC) efficacy trial, indication
of drug use was based on APACHE II scores.58-62 Barochia et al. investigated
efficacy of use of an anti-inflammatory drug in sepsis where the dose of study
drug was linked to the subjects predicted mortality rates.60 Such use of severity
scores in drug trials is not seen commonly as these scores were not designed for
this purpose.
Organ dysfunction scores were introduced to include morbidity in the
assessment of patient outcomes and ICU performance and are not usually used
for mortality predictions. Many investigators have included organ failure score
SOFA for drug efficacy trials.63,64
Decision Support
Though the scoring systems do not predict mortality in an individual critically ill
patient, they are often used for discussion and counseling regarding the patient’s
likely outcome. The scoring systems are not precise enough to be relied upon for
decisions regarding any specific treatment or for limiting of life-support therapies
or for triaging in the emergency department, especially as an indication for ICU
admission in low-risk patients.
CONCLUSION
APACHE, SAPS and MPM are the most frequently used general scoring systems
for assessment of severity of illness and outcome predictions, and SOFA is most
used organ dysfunction scoring system. Different scores were developed for
specific purposes; outcome prediction models are better than organ dysfunction
scores in predicting mortality but cannot do assessment of the severity of organ
failure. They should be used to support the clinical evaluation rather than replace
it. These models allow stratification of patients for outcome and drug efficacy
research, performance assessment, benchmarking, resource management, and
dissemination of outcome results. None of the models perfectly predicts the
outcome for an individual patient. Organ or disease-specific scores perform
better in selected patients or situations (e.g., the Glasgow Coma Scale, Injury
Severity Score, Model for End-stage Liver Disease Score. There is no gold standard
amongst the scoring systems. Each-system has limitations and the selection of
model to be used should be based on factors like availability, applicability and
suitability.
All the scoring systems will need to be updated periodically because
of changing patient and disease profile, newer technology, diagnostic and
therapeutic agents’ availability, and newer trends in critical care practice.
KEY POINTS
• S coring systems have been in use in intensive care units since 1981.
• Predictive scoring systems are typically used to predict important hospital outcome,
typically mortality in general intensive care unit (ICU) patients. They are not accurate
when used in certain disease groups or specialized ICUs. Outcome predictions are
intended for groups and not individuals.
• General outcome prognostic systems for adults are the APACHE II, III, and IV; SAPS II and
III; and MPM II and III, and general organ dysfunction scores such as SOFA, MODS, LODS.
• Newer versions are complex and costly but predict mortality more accurately than
simplified models.
• General severity-of-illness scores have been used to characterize disease severity and
degree of organ dysfunction, outcome prediction, resources allocation, performance
evaluation, benchmarking, and research.
• No single instrument has convincing or proven superiority to another in its ability to
predict mortality, although APACHE systems tend to be more accurate than others.
• The choice between scoring systems remains largely individualistic. APACHE II and
SOFA are the most used scoring systems. They should be used to support the clinical
evaluation rather than replace it.
• Model accuracy deteriorates with time and needs to be periodically updated and
retested.
• It is essential to be familiar in the use of a scoring system model to ensure reliable results.
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impact of methods of assessment and potential confounders. Chest. 2008;133:1319-27.
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physiology and chronic health evaluation IV in Dutch intensive care units and
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2009;13(Suppl 1):P510DOI: 10.1186/cc7674.
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in a large multicenter cohort of admissions to adult, general critical care units in the
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25. Metnitz PG, et al. Prognostic performance and customization of the SAPS II: results of
a multicenter Austrian study. Simplified Acute Physiology Score. Intensive Care Med.
1999;25:192-7.
26. Minne L, Eslami S, de Keizer N, et al. Effect of changes overtime in the performance
of a customised SAPS-II model on the quality of care assessment. Intensive Care Med.
2012;38:40-6.
27. Haaland A, Lindemark F, Flaatten H, et al. A calibration study of SAPS II with Norweigian
intensive crae registry data. Acta Anaesthesiol Scand. 2014;58:701-8.
28. Katsounas A, Kamacharova I, Tyczynski B, Eggebrecht H, et al. The predictive
performance of the SAPS II and SAPS III scoring systems: A retrospective analysis. J
Crit Care. 2016;33:180-5.
29. Ledoux D, Canivet JL, Preiser JC, et al. SAPS 3 admission score: An external validation
in a general intensive care population. Intensive Care Med. 2008;34:1873-7.
30. Poole D, Rossi C, Anghileri A, et al. External validation of the simplified acute
physiology score (SAPS) III in a cohort of 28,357 patients from 147 Italian intensive
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31. Nassar AP Jr, Mocelin AO, Nunes AL, et al. Caution when using prognostic models: a
prospective comparison of 3 recent prognostic models. J Crit Care. 2012;27:423.e1.
32. Poole D, Rossi C, Latronico N, et al. Comparison between SAPS II and SAPS 3 in
predicting hospital mortality in a cohort of 103 Italian ICUs. Is new always better?
Intensive Care Med. 2012;38:1280-8.
33. Rothen HU, Stricker K, Einfalt J, et al. Variability in outcome and resource use in
intensive care units. Intensive Care Med. 2007;33:1329-36.
34. Metnitz B, Schaden E, Moreno R, et al. Austrian validation and customization of the
SAPS 3 admission score. Intensive Care Med. 2009;35:616-22.
35. Liu V, Turk BJ, Ragins AI, Kipnis P, Escobar GJ. An electronic simplified acute physiology
score-based risk adjustment score for critical illness in an integrated healthcare system.
Crit Care Med. 2013;41:41-8.
36. Lemeshow S, Klar J, Teres D, Avrunin JS, et al. Mortality probability models for patients
in the intensive care unit for 48 or 72 hours: a prospective, multicenter study. Crit Care
Med. 1994;22:1351-8.
37. Higgins TL, Kramer AA, Nathanson BH, et al. Prospective validation of the intensive
care unit admission. Mortality Probability Model (MPM0-III). Crit Care Med. 2009;
37:1619-23.
38. Vincent JL, de Mendonça A, Cantraine F, et al. Use of the SOFA score to assess the
incidence of organ dysfunction/failure in intensive care units: results of a multicenter,
prospective study. Working group on "sepsis-related problems" of the European
Society of Intensive Care Medicine. Crit Care Med. 1998;26:1793-800.
39. Moreno R, Vincent JL, Matos R, et al. The use of maximum SOFA score to quantify
organ dysfunction/failure in intensive care. Results of a prospective, multicentre study.
40. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus
Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:801-10.
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the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
JAMA. 2016;315:762-74.
42. Shankar-Hari M, Phillips GS, Levy ML, et al. Developing a new definition and assessing
new clinical criteria for septic shock: For the third International Consensus Definitions
for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:775-87.
43. Metnitz PG, Lang T, Valentin A, Steltzer H, Krenn CG, Le Gall JR. Evaluation of the
logistic organ dysfunction system for the assessment of organ dysfunction and
mortality in critically ill patients. Intensive Care Med. 2001;27:992-8.
44. Beck DH, Smith GB, Pappachan JV, et al. External validation of the SAPS II, APACHE II
and APACHE III prognostic models in South England: A multicentre study. Intensive
Care Med. 2003;29:249-56.
45. Livingston BM, MacKirdy FN, Howie JC, Jones R, Norrie JD. Assessment of the
performance of five intensive care scoring models within a large Scottish database. Crit
Care Med. 2000;28:1820-7.
46. Kramer AA, Higgins TL, Zimmerman JE. Comparison of the mortality probability
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evaluation IV hospital mortality models: implications for national benchmarking. Crit
Care Med. 2014;42:544-53.
47. Peres BD, Melot C, Lopes FF, Nguyen BV, Vincent JL. The multiple organ dysfunction
score (MODS) versus the sequential organ failure assessment (SOFA) score in outcome
prediction. Intensive Care Med. 2002;28:1619-24.
48. Zygun D, Berthiaume L, Laupland K, Kortbeek J, Doig C. SOFA is superior to MOD
score for the determination of non-neurologic organ dysfunction in patients with
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49. Brinkman S, Abu-Hanna A, van der Veen A, Jonge ED, et al. A comparison of the
performance of a model based on administrative data and a model based on clinical
data: Effect of severity of illness on standardized mortality ratios of intensive care units.
Crit Care Med. 2012;40:373-8.
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51. Marik PE, Hedman L. What’s in a day? Determining intensive care unit length of stay.
Crit Care Med. 2000;28:2090-3.
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simplified acute physiology score II: assessing their value in predicting length of stay
and comparison to APACHE IV. Chest. 2009;136:89-101.
53. Kramer AA, Zimmerman JE. A predictive model for the early identification of patients
at risk for a prolonged intensive care unit length of stay. BMC Med Inform Decis Mak.
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54. Nishijima DK, Sena MJ, Holmes JF. Identification of low-risk patients with traumatic
brain injury and intracranial haemorrhage who do not need intensive care admission.
Trauma. 2011;70(6):E101-7.
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with mortaility among older patients with pneumonia. JAMA. 2015;314(12):1272-9.
56. Beck DH,Smith GB, Taylor BL. The impact of low-risk intensive care unit admissions
on mortality probabilities by SAPS II, APACHE II and APACHE III. Anesthesia. 2002;
57:21-6.
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severe sepsis and septic shock. N Engl J Med. 2001;345:1368-77.
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activated protein C for severe sepsis. N Engl J Med. 2001;344:699-709.
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antibiotic therapy for serious infections associated with sepsis and septic shock is
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Med. 2010;38:1651-64.
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B hemoperfusion in patients with septic shock due to peritonitis: a multicenter
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sepsis: Protocol for a randomized controlled trial. Trials. 2014;15:199.
CHAPTER 6
Transdermal Drug Delivery
Aruna Parameswari, Akilandeswari Manickam
INTRODUCTION
The transdermal delivery of drugs is an ancient science that has evolved
over the years incorporating innovative methodologies and introducing
multiple effective drug formulations for maximizing the therapeutic benefits
to mankind. The use of skin as a route of drug delivery dates back to the
era of Galen (129–199 AD); the father of pharmacy who developed the cold
cream, for application on the skin which is the basic model behind the present
transdermal delivery system.1 The skin being an easily accessible organ with a
surface area of 1.5–2 m2, comprising 10% of the body mass is used as a primary
route for drug administration in this system.2 The function of the transdermal
delivery system is to deliver a fixed amount of drug over a specific time period
from an adhesive medicated patch of predefined area into the skin. The
target site of the drug is either localized, restricted to the site of application or
systemic, mediated by capillary absorption. The primary difference between a
transdermal drug and dermal medication is that the former is applied on intact
skin without any skin disease and has ingredients to promote diffusion and
absorption of the drug.3
This method eliminates the need for multiple injections, avoids first pass
metabolism, and is unaffected by the presence or absence of GIT problems that
affect the absorption and serum levels of the drug. The noninvasive nature,
ease of administration and the maintenance of steady plasma concentration
of drug as long as the patch remains results in desirable therapeutic effects
for a prolonged period thereby improving patient compliance.3 However, all
drugs cannot be administered through this route as the innate barrier function
of the skin; physiochemical properties of the drug and blood flow to the skin
influence the kinetics of absorption via the skin. Understanding the skin
physiology, pathways of drug transport, and the factors affecting permeation
across the layers of skin are crucial to optimize this mode of drug delivery.2-4
Anesthesiologists should possess knowledge about the pharmacokinetic
principles, indications, limitations and the recent innovations regarding
transdermal drug delivery for relevant choice and use in clinical practice. They
have a definitive role in providing topical anesthesia, acute pain management,
analgesia for chronic pain of musculoskeletal system, cancer and neuropathic
pain.5
Transdermal Drug Delivery 69
PHYSIOLOGY OF SKIN AND PATHWAYS

OF DRUG TRANSPORT
The skin consists of epidermis, dermis and the appendages. The outermost layer
of the skin is the epidermis which has 5 layers from outside to inside namely—
the stratum corneum, stratum lucidum, granulosum, spinosum, and basale.2
The outermost layer, the stratum corneum contributes to the barrier function of
the skin and offers maximal resistance for permeation of drugs. This layer has
multiple layers of anucleated cells corneocytes which are arranged like bricks
interspersed with the lipid matrix. The corneocytes are rich with protein keratin.
The lipid matrix is unique as they are multilamellar in nature possessing both
lipophilic and aqueous components. They constitute an important pathway of
drug transport in between the corneocytes. The other layers of the epidermis
without the stratum corneum are referred to as viable epidermis as they contain
nucleated cells—melanocytes, Langerhans cell, Merkel cell and keratinocytes.
The thickness of the stratum corneum is 10–15 µm which swells up to 40 µm when
hydrated. The dermis is 3–5 mm thick and is comparatively more hydrophilic
than the epidermis. It has the sweat glands, hair follicles, nerve endings and is
rich in capillary network which is the main site for systemic absorption. Hence,
drugs with balanced lipophilic and hydrophilic affinities are ideal for permeation
across the layers of the skin to reach the target site of systemic absorption.2-4
Passive diffusion of drugs is the primary mechanism for transport of molecules
through the skin.
The transport of drugs across the epidermis to reach the target site occurs by
three pathways:
1. Intercellular: Diffusion occurs through the lipid matrix present between the
corneocytes. The drug partitions and diffuses through the polar and lipophilic
phases of the bilamellar matrix sequentially, to gain access to the deeper layers
of the skin. This forms the major pathway for drug penetration across the skin.
2. Transcellular: Diffusion is via the corneocytes which are hydrophilic and
made of protein keratin.
3. Transappendageal: Diffusion is via the hair follicles and sweat glands. It forms
the least resistant and shortest pathway for drug permeation, enabling the
transfer of relatively bigger molecules. But they contribute only to 0.1% of the
skin surface area, and hence this pathway is of minor importance.4,5
PHARMACOKINETICS OF TRANSDERMAL DELIVERY

The transdermal delivery of drugs involves a series of steps in a sequential manner
such as release of drugs from the source, adsorption to skin surface, diffusion
through the layers of stratum corneum, partitioning of drug in different layers of
the skin and ultimately reaching the cutaneous circulation. So there is a period
of delay from the time of application of patch till the minimum concentration
and steady-state levels of the drug are achieved in the plasma for the intended
therapeutic benefits. There is no variability in the serum level once steady
concentration is achieved, as long as the patch is present. The decline in drug
levels following patch removal is based on the drug’s context sensitive half time
and the presence of drug depots in the skin.5
Release of drug from the patch is driven by the concentration gradient between
the patch and the skin. Passive diffusion of drug molecules and partitioning in the
layers of the stratum corneum is determined by the physiochemical properties of

the drug. The rate of transfer of drugs (J) is determined by the formula,
dQ DPCv
J= =
dt h
where Q is the amount of drug permeating a unit area of skin, D is the diffusion
coefficient of the drug in the skin, P is the partition coefficient of the drug between
the stratums corneum and the vehicle, Cv is the concentration of the drug, and
h is the distance traveled or the thickness of the membrane.
The following properties of drugs enable ideal transdermal delivery:
• Highly potent drugs
• Requirement less than 20 mg/day
• Half life less than 10 hours
• Molecular weight < 400 Daltons
• Intermediate lipophilicity
• pH between 5.0 and 9.0
• Melting point < 200°C
• Partition coefficient Log P (octanol–water) between 1.0 and 4.0
• Hydration of the skin improves permeation acting as enhancers.
Various physical methods, chemical enhancers, nanocarriers, use of
ultrasonic, electrical, magnetic and laser waves are employed as a component
of the patch or transdermal system to facilitate drug movement.2,4 They act
by increasing the driving force for diffusion and by disrupting the structure of
stratum corneum into low resistance pathways for facilitated diffusion. Based
on the level of invasiveness and reversibility of the structure and organization
of the stratum corneum, they have been classified as first, second and third
generation delivery systems. The properties of the drug influence the diffusion
in first generation system. The second generation systems create pathways
for diffusion of drugs by creating spaces between the corneocytes, inducing
fluidity of the intercellular lipid matrix and improving the solubility of the
drug in the skin. For instance the chemical enhancers-propylene glycol and
ethanol alter the solubility of the skin for the drug; azone induces fluidity of
the lipid matrix to facilitate cutaneous transport. The addition of chemicals,
use of supersaturated solution, iontophoresis, formation of eutectic mixture
and application of heat are all passive permeation enhancers that do not
disrupt the stratum corneum. The third generation systems induce irreversible
change in the stratum corneum to hasten the transport by use of microneedles,
laser ablation, electroporation, jet injectors, etc. to the skin.6-8 This strategy is
essential for the transport of macromolecules, e.g. insulin, peptide hormones,
etc.
DESIGN AND TYPES OF TRANSDERMAL PATCHES

The basic components of transdermal patch include release liner, adhesive,
drug, enhancers, membrane and the backing layer, all of which are arranged in
layers.2,5 The adhesive is made of acrylic, silicone or polyisobutylene and ensures
adherence of the patch to the skin. The release liner protects the drug during
storage and is removed prior to application. The backing membrane is made of
polymers–vinylpolyethylene, polyester, etc. This layer should be resistant to the
effects of chemical enhancer to prevent spillage of the drug outside. The oxygen
and moisture transmission via the backing layer should be adequate to ensure
hydration of the skin. The membrane determines the rate of release of the drug
and is made of ethylene vinyl cellulite, polyurethane or silicone and is the primary
factor that modulates the drug flux from the patch.9
Single Layered Adhesive Patch

The drug is a part of the adhesive layer which adheres the patch to the skin and
controls the release of the drug. It is surrounded by the liner and the backing
membrane.
Multilayered Adhesive Patch

This type of patch is similar to the single layer patch except for the presence of
two layers of adhesive with the drug, the layers being separated by a membrane.
The one near the skin is for immediate release and the other layer above the
membrane acts as the reservoir.
Reservoir System
There is a separate reservoir containing the drug as solution, gel or as suspension
which is located between the backing layer and the membrane. The rate of flux of
drug from the patch to the skin is determined by the thickness and permeability
of the membrane. It is not recommended to cut and use these types of patches as
the concentration of the drug in the patch cannot be predicted.
Matrix System
The drug is homogeneously dispersed in a polymer matrix or viscous adhesive
that is hydrophilic or lipophilic in nature and is in direct contact with the skin. The
adhesive forms a part of the matrix and is responsible for containing the drug, its
release, and adhesion. Matrix patches are relatively thinner. The amount of drug
released depends on the concentration of the drug and the surface area of the
patch. The chance for accidental overdosing and abuse is negligible as the drug is
uniformly distributed in the matrix.
Hybrid Patches
It is a combination of reservoir and matrix type patch where the drug is suspended
in the form of a reservoir and then spread uniformly in a lipophilic polymer and
made into microspheres.
DRUGS USED AS TRANSDERMAL PATCHES

The first patch approved for usage was scopolamine for motion sickness.6 Over
the years, there has been an increase in the number of transdermal products
approved for various medical disorders. Innovations in technology paved
way for effective use and design of transdermal drugs overcoming the barriers
and limitations of this system. The list of patches available and their clinical
indications are given in Table 6.1. Commonly used drugs include transdermal
opioids, transdermal NSAIDs and transdermal local anesthetics.
72
Table 6.1 Available analgesic patches, size of the patch, drug release rate and indications for use
Drug Trade name Area of the patch Total amount of drug Dose/hr Indication
Fentanyl Fentalis, 5–42 cm2 2.1–16.8 mg 12.5–100 μg/hour
Duragesic,
Mezolar
Buprenorphine BuTrans 20.25/30.6/ 5/10/20 mg 5/10/20 μg/hour for Analgesia for cancer pain
51.84 cm2 7 days
TransTec 25/37.5/50 cm2 20/30/40 mg 35/52.5/70 μg/hour for Chronic non-cancer pain
4 days
Lignocaine +Tetracaine Rapydan, Total patch size—50 cm2 70 mg of each NA Topical anesthesia for
Synera Active area—10 cm2 venous cannulation
Lignocaine + Prilocaine EMLA Total patch size—40 cm2 2.5% of each active in NA Excision of skin lesion
Active area—10 cm2 each 1 g patch
Diclofenacepolamine Voltrol 10 cm × 14 cm 140 mg 50/100 mg for 12 hours Acute local sprains,
tendinitis, osteoarthritis
Lidocaine 5% Versatis 10 cm × 14 cm 700 mg 12 hours/day for weeks Neuropathic pain
Table 6.2 Physiochemical properties of opioids

Drug characteristics Morphine Buprenorphine Fentanyl
Molecular weight 337 468 286
Aqueous solubility (µg/mL) 1:5000 1:1000–10,000 1:30–100
Octanol/water coefficient –0.1 4.98 2.3
(Log P)
Skin flux (µg /cm2) 0.006 1.4 1
Transdermal Opioids
Fentanyl and buprenorphine are the most commonly available and used
transdermal opioids, as the physiochemical properties are conducive for
transdermal absorption (Table 6.2).
Fentanyl
Fentanyl patches are available in strengths of 12, 25, 50, 75 and 100 µg/hour
which last for a duration of 72 hours. They are available as both reservoir and
matrix type patches with similar bioequivalence. The absorption from the arm,
chest and abdomen are similar with least values noted from application on the
sole. Increase in body temperature to 40°C due to fever or application of heat
from external source-warmers increases the concentration of fentanyl by three
fold, resulting in accidental overdose and respiratory depression. The serum
levels of fentanyl are maximum at 12–24 hours after application of the patch.
Hence, supplementation is needed during this window period and the analgesic
efficacy is assessed only after 24 hours. The elimination half life is 22 hours after
patch removal due to the sustained release from the skin depots, demanding a
cautious approach for the use of other opioids. Metabolism is by CYP3A enzyme
and co-administration of drugs such as ketoconazole, amiodarone, verapamil or
clarithromycin delays the elimination of fentanyl.5,9-11
Buprenorphine
This semisynthetic opioid is 60 times more potent than morphine and acts as a
partial agonist at the mu (µ) receptors, antagonist at the kappa (k) receptors with
high affinity for both receptors. It also is a weak delta receptor antagonist. The
metabolite nor-buprenorphine has agonist activity at the delta receptors located
in the pain fibers of the skeletal system, which is responsible for relieving pain of
musculoskeletal origin. Buprenorphine is available either as a 7 day patch at 5, 10,
20 µg/hr or as a 3 day patch at 35/52.5/70 µg/hr. The ceiling effect, noted at a dose
of 16 mg/day is rare as the maximum dose after application of two patches of 70
µg/hr simultaneously results only in a dose of 3.36 mg/day.12
The steady-state concentration of the drug in plasma is achieved at 48 hours
after patch application with a terminal half-life of 26 hours. The efficacy of
analgesia is thus assessed after 48 hours and patients need to be monitored for
30 hours after the removal of the patch to detect the side effects. The absorption
of buprenorphine is increased by 26% in the upper back compared to other
conventional sites and the absorption is least from the patella. The site of patch
application needs to be changed each time and the same site should not be
chosen for application in the subsequent 2–3 weeks in view of altered absorption
kinetics. Dose adjustments are not needed in elderly and in patients with renal
failure. It is contraindicated in patients with liver disorders, impaired respiratory
status and patients on therapy with MAO inhibitors.
Erythema, pruritus and edema are the most common side effects with
transdermal opioids. Constipation, nausea and vomiting are relatively less
with transdermal opioids compared to oral morphine. Among the transdermal
opioids, buprenorphine has comparatively lesser adverse events than fentanyl.13
Uses
Transdermal opioids have a definitive role in cancer patients with moderate-to-
severe pain. Neuropathic pain in cancer responds well to transdermal opioids.13
The presence of nausea, vomiting and malabsorption in cancer patients affects
the oral bioavailability and this can be overcome with transdermal delivery of
opioids. The required dose for analgesia is reduced, thus minimizing side effects.
The quality of analgesia is superior as there are no fluctuations in the serum
level after the initial lag period. Mobility of the patient is unaffected, unlike other
invasive methods of patient controlled analgesia.
Studies have shown the use of transdermal buprenorphine to provide
equivalent pain relief to oral morphine with less break through pain and sleep
disturbances. The European Association for Palliative Care advises the use of
transdermal opioids in patients who are pain free with stable dose of oral opioid
medications. The fentanyl patch is approved for usage in children above the age
of 2 years for chronic cancer pain. Buprenorphine patch is not recommended in
children below 18 years of age.13,14
Transdermal opioids are an effective alternative to nonopioid analgesics
in the treatment of chronic non-malignant pain, osteoarthritis, back pain and
rheumatoid arthritis.9
Initiations and Titrations of Transdermal Opioids

• The transdermal opioids are prescribed to patients who are pain free and
stabilized with oral opioid medications.
• The 24 hr morphine requirement is calculated for each patient based on the
conversion dose from Table 6.3.
• The equivalent dose of transdermal patch is chosen for providing analgesia.
• The oral dose of opioid is continued at the time of patch application as there is
delay in achieving the minimum effective drug level by the transdermal route.
Table 6.3 Conversion rates for transdermal fentanyl

Fentanyl (µg/hour) Oral morphine Oxycodone (µg/day) Hydromorphone
(µg/day) IM/PO (µg/day) IM/PO
25 30–90 40 15
50 91–150 80 30
75 151–210 120 45
100 211–270 160 60
Vigilant monitoring for the side effects related to overdose and under dosing
is mandatory during the transitional phase. For example, the modification in
the dose of transdermal fentanyl patch is done after 72 hours. It is upgraded to
the next available increased dose, if there is a need for more than 3 rescue doses
within a period of 24 hours.14
Transdermal Nonsteroidal Anti-inflammatory Drug

About 1% Diclofenacepolamine patch provides pain relief in acute sprain, sports
injuries and osteoarthritis.15 The analgesic effects are noted at 3 hours, mediated
by the localized effects at the site of application. Transdermal NSAID was found
to be more superior when compared to oral NSAID in providing analgesia
for osteoarthritis.15,16 Relief of postoperative pain following dental extraction,
laparoscopic gynecological surgeries and arthroscopic shoulder surgeries was
better when compared to oral NSAIDs with less systemic side effects and better
patient compliance.17,18
Transdermal Local Anesthetics

Lignocaine, tetracaine, amethocaine and prilocaine are the most commonly
used topical local anesthetics.19 The eutectic mixture is a combination of local
anesthetics in 1:1 ratio, which decreases the melting point of the mixture, forming
an oil/water emulsion with improved skin penetration properties. Eutectic
mixture of local anesthetics (EMLA), which contains 2.5% lignocaine and 2.5%
prilocaine, produces excellent cutaneous anesthesia when applied 60–90 minutes
on intact skin. The amount of systemic absorption with EMLA varies with the site,
area, duration of application and the mass of the drug. A single dose of 1 g EMLA
can be used safely in term neonates without the risk of methemoglobinemia. The
recommended dose of EMLA in children is given in Table 6.4.
Transdermal local anesthetics are indicated for painless venous cannulation,
skin biopsies, punch biopsy and bone marrow aspiration. Excision of skin lesions
and laser-assisted removal of lesions from the skin are accomplished without
pain by the use of topical local anesthetics.
Five Percent Lignocaine Patch

It is used to relieve the neuropathic pain of postherpetic neuralgia.20 The patch is
applied over the area of skin with maximum pain for a period of 12–16 hrs/day.
The therapeutic benefits are observed within a couple of days and the patch is
Table 6.4: Recommended maximum dosages of EMLA in full‐term neonates, infants, and
children
Age group Maximum dose (g) Maximum skin area (cm2)
0–2 months 1 10
3–11 months 2 20
1–5 year 10 100
6–11 year 20 200
gradually weaned over weeks. It does not produce cutaneous anesthesia like other
topical local anesthetics as the large myelinated Aβ fibres are not inhibited by
the sustained release of low concentration of lignocaine. In spite of their efficacy
being proven, they are not recommended as the first-line drugs for neuropathic
pain.21
Synera or Rapydan Patch

It is an eutectic mixture of lignocaine 70 mg and tetracaine 70 mg with controlled
heat-assisted drug delivery technology incorporated in the patch. The patch
contains a mix of iron powder, carbon, sodium chloride and wood which on
exposure to air generates heat by exothermic reaction. The temperature rises by
5°C, to a maximum level of 40°C and improves the blood flow and permeability
of local anesthetics in the skin, resulting in rapid onset of cutaneous anesthesia.
Studies with synera patch have shown to produce dermal anesthesia at 20–30
minutes from the time of application with a maximal anesthetized skin depth of
8.22 mm for a duration of 100 minutes.22 The patch was studied in children more
than 3 months of age for venous cannulation and was found to result in lesser
pain scores with 100% success rate for vein entry, establishing its safety and
efficacy in pediatrics. The plasma levels of lignocaine and tetracaine in children
were 16.8 ng/mL and less than 0.9 ng/mL respectively which is well below the
toxic level. The patch has to be removed prior to entry into an MRI suite due to
the presence of iron in the system.19,23-25
NOVEL METHODS OF TRANSDERMAL

DRUG DELIVERY
Iontophoresis
It is a second generation transdermal delivery system that facilitates drug
movement by the application of low intensity electric current.26 Water soluble,
low molecular weight drugs, capable of ionization are suitable for iontophoresis.
Unlike passive permanent system, the induction of therapeutic effects are quicker,
contributing to their role in acute pain management.
The unit has a microprocessor, power source and the electrode components-
cathode and anode. The drug is placed in the controller unit according to the
charge of the molecule. On activation, the current is delivered causing the
movement of ions from the controller unit to the skin. The circuit is completed by
the movement of ionized drug to the respective electrodes based on the charge
of the ions. Improvement in skin permeability after current application further
promotes cutaneous transport of charged drugs. There is a swift movement of a
fixed quantity of the drug across the skin with no passive absorption in between
and levels decline rapidly after the patch removal, unlike the conventional
system.26,27 Studies have shown fentanyl delivered by iontophoresis to be
equivalent to IV administration of the same dose.28-30 The intensity of current,
dose in the patch, pH that influences the degree of ionization of the drug, and the
surface area of patch determine the dose delivered by iontophoresis. The drugs
suitable for iontophoresis are fentanyl, lignocaine, GnRH analogs, parathyroid
hormone and NSAID.
Fentanyl iontophoretic transdermal system is a compact patch, worn on

the upper chest or arm. It has a drug unit, controller unit, hydrogel and power
source that delivers 170 µA current. On activation by the patient, a fixed dose of
40 µg of fentanyl is delivered over 10 minutes with a control limit of 6 doses per
hour. The system works for 24 hours or to a maximum of 80 doses and shuts off
spontaneously. It is a needle free, patient-controlled transdermal system that
provides analgesia quickly without any lag period. The maximum serum level of
fentanyl is attained at 39 minutes with an elimination half life of 11 hours, similar
to intravenous administration of the same dose. Several studies have shown that
the use of fentanyl iontophoresis provided analgesia that was superior to placebo
and equivalent to IVPCA in patients who underwent major orthopedic and
abdominal surgery.28-32 In addition, this method of pain control was preferred
by patients as assessed by the validated PGA score-patient global assessment
of pain.31 Since the dose of fentanyl is preprogrammed, adjustment of dose is
impossible after application which may be a limitation.
Lignocaine iontophoresis produces dermal anesthesia to a depth of 6–10 mm.
The lidosite is an FDA approved inotophoretic system consisting of a 5 cm2 patch
of lignocaine 10% and 0.1% epinephrine. It provides dermal anesthesia within 10
minutes and can be used for IV cannulation, superficial procedures on the skin
and needle stick for withdrawal of blood.
Retrospective evaluation of children treated with dexamethasone
iontophoresis for juvenile rheumatoid arthritis involving temporomandibular
joint showed significant improvement in mouth opening and resolution of pain.
This noninvasive treatment was suggested as an alternative to intra-articular
steroid injection. Patients with Achilles tendon injury treated with dexamethasone
iontophoresis for 2 weeks with a time interval of 2–4 days showed significant
improvement in their physical activity.33
Ultrasound
The use of ultrasonic waves to transport drugs across the skin is termed as
phonopheresis.34 The waves induce biological effects such as increase in
temperature, gas bubble formation with opening of aqueous channels and acoustic
streaming effects that disrupts the lipid layer of the stratum corneum promoting
transport. The low frequency waves in the range of 20–100 KHz, (especially 20
KHz) are more efficient and 1000 times better than the high frequency waves
for transdermal drug delivery. The positive effects on permeation persist for
a period of 48 hours, unlike other techniques. Ultrasound has both invasive
and noninvasive effect on transdermal drug delivery. The thermal effects are
relatively non invasive where as the cavitational effects of ultrasound are invasive,
categorizing it as a third-generation transdermal system.
The sono prep is an FDA approved device for delivering ultrasound waves that
has a microprocessor, hand piece and disposable cartridge. The USG treatment
of skin with this device for a period of 5 minutes followed by local anesthetic
application, resulted in dramatic reduction in the onset time of cutaneous
anesthesia allowing painless cannulation after 5 minutes in both children and
adults.34-36
Invasive Methods
These include the use of microneedles, electroporation, laser ablation,
magnetopheresis and use of hybrid methods (combination of chemical and
physical methods) for improving the efficiency of skin penetration.37
Microneedles of size 200–700 microns in length, made of silicone or metals,
are used to selectively penetrate the stratum corneum without causing pain,
by avoiding the nerves present in the dermis. The needles are coated with the
active drug component or used as hollow channels for transport of drugs. This
technique is suitable for macromolecular transport, for example, vaccines or
insulin.37
Thermal ablation, which involves heating the skin to 100°C for seconds
creates microchannels for drug transport, by vaporization of the water content
in the stratum corneum. Passport system uses this technology in the patch, for
delivering hydrophilic molecules like morphine, hydromorphone and fentanyl.
The size of the patch is very small (1 cm2) and it delivers fentanyl at a higher
concentration than the conventional patch.
Electrical pulses of high voltage can be applied for a fraction of a second to
form channels for transport of drugs. The use of lignocaine-coated microneedles
along with electroporation referred to as “Painless Laser Epidermal System”
achieves a very high concentration of local anesthetic within a minute for piercing
ears in animal experiments.37
Nanocarriers
The use of nanocarriers for targeted delivery of drugs at desired therapeutic levels
in a controlled manner is the principle of this technology.38 Nanoparticles are
synthetic or natural polymers which are biocompatible, biodegradable without
any tissue reactivity or toxicity. They act as drug carriers and promoters of skin
permeation and ensure sustained and controlled release of the drug at the target
sites for prolonged duration of action. The size of the nanoparticles should be less
than 50 nm for acting as carriers. Ethosomes are nanocarriers with ethanol as an
additional component for permeation and transferosomes are rapid transporters
that possess elastic properties and are amenable to change in size and shape with
flexibility, facilitating diffusion through the skin.37,38
Liposomes
They are spherical vesicles of different sizes (0.025–1 µm in diameter), possessing
a phospholipid envelope with an aqueous core. They are biocompatible, enclose
both lipophilic and hydrophilic drug molecules and are pH and temperature
sensitive. The vesicles can be large or small, unilamellar or multilamellar in
morphology. The size of the liposomes should be less than 500 nm diameter for
penetration through the skin. The liposome-mediated transport ensures drug
delivery at the site of action, thereby reducing the total mass of drug in the system.
LMX4 is a 4% liposomal topical lignocaine which has an onset of action of
15–30 minutes and has been used for relieving pain in minor cuts, abrasion and
irritation from insect bite. The pain scores during meatotomy were less in children
who received liposomal lignocaine compared to that of lignocaine prilocaine
combination. The absence of venoconstrictive properties, shorter onset of action
with minimal systemic absorption and ease of application without occlusive

dressing makes it ideal for topical anesthesia compared to EMLA.38,39
CONCLUSION
The use of skin as an interface provides needle-free access for delivery of drugs,
resulting in localized and systemic effects. Modulation of cutaneous transport by
different techniques aids in overcoming the barriers for cutaneous absorption,
enhances the induction of pharmacological effects and prolongs the duration of
action. Research for inclusion of all local anesthetics and analgesics would help
in maximal benefits for all groups of patients in the perioperative period.
KEY POINTS
• Transdermal route paves the path for noninvasive, convenient mode of drug delivery
providing consistent plasma levels of drug, resulting in beneficial therapeutics.
• Transdermal delivery of opioids, NSAIDs and local anesthetic agents are the most
commonly used drugs relevant to anesthesiologist’s practice.
• Opioid patches are effective in the treatment of chronic malignant pain and non-
malignant pain of chronic inflammatory disorders such as rheumatoid arthritis, back-
pain etc.
• Local anesthetic patches are indicated for venous cannulation, superficial procedures
on the skin and for biopsies. Their role in relieving pain of neuropathic origin is under
investigation.
• Iontophoresis is a unique transdermal system, providing quick onset of action and
plays a valuable role in acute pain management.
• The novel methods for improving skin permeation by nanocarriers, ultrasonography
and liposomes are the future areas of research, investigation and review for expanding
their role in acute pain management.
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16. Banning M. Topical diclofenac: clinical effectiveness and current uses in osteoarthritis
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17. Bhaskar H, Kapoor P, Ragini. Comparison of transdermal diclofenac patch with
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18. Alessandri F, Lijoi D, Mistrangelo E, Nicoletti A, Crosa M, Ragni N. Topical diclofenac
patch for postoperative wound pain in laparoscopic gynecologic surgery: a randomized
study. J Minim Invasive Gynecol. 2006;13(3):195-200.
19. Delgado-Charro MB, Guy RH. Effective use of transdermal drug delivery in children.
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20. Hans G, Robert D, Verhulst J, Vercauteren M. Lidocaine 5% patch for localized
neuropathic pain: progress for the patient, a new approach for the physician. Clinical
pharmacology: advances and applications. 2010;2:65-70.
21. Khaliq W, Alam S, Puri NK. Topical lidocaine for the treatment of postherpetic
neuralgia. Cochrane Database Syst Rev. 2007;2:CD004846.
22. Wallace MS, Kopecky EA, Ma T, Brophy F, Campbell JC. Evaluation of the depth and
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23. Sawyer J, Febbraro S, Masud S, Ashburn MA, Campbell JC. Heated lidocaine/tetracaine
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undergoing meatotomy. J Urol. 2004;172:1760-1.
CHAPTER 7
Peripheral Opioid Receptors
RP Gehdoo, Harshita Singh
INTRODUCTION
Opioids are potent analgesics and are widely used in clinical practice to control
both acute and chronic pain. The mediation of opioid analgesic action has been
an extensively researched topic worldwide. Opioid receptor model was first
demonstrated in the year 1960 and their existence was believed to be exclusively
within central nervous system (CNS). In 1987, Russell’s et al. in Germany,1
showed the presence of opioid receptors on nerve fibers in the knee joint of
the cat and observed that locally administered opioid agonists decrease the
frequency of spontaneous discharges in the nerve fibers with small diameters.
It was postulated that opiates, by binding to opiate receptors on primary afferent
fibers in peripheral locations may exert a peripheral “analgesic” effect.1 Later,
peripheral neurons, few cells of neuroendocrine system (pituitary, adrenal),
immune and ectodermal cells were also shown to express opioid receptors.2
Peripheral opioid receptors have an important role in controlling and
modifying pain and inflammation. At the site of injury, primary afferent neurons
convert noxious stimuli into action potentials. The cell bodies of these neurons
are present in the trigeminal and dorsal root ganglia (DRG) and give rise to Aδ
and C fibers. After modulation within the primary afferent neurons and spinal
cord, nociceptive signals reach the brain, where they are finally recognized
as “pain,” within the context of cognitive and environmental factors.3 The
therapeutic implication here lies in the fact that primary afferent neurns form
the primary source of generation of nociceptive impulse and their inhibition
would prevent subsequent events in the generation of nociceptive impulse,
sensitization and plasticity. Opioids group of compounds form the most powerful
drugs to abolish severe pain, but their use is hindered by side effects which may
be bothersome such as nausea, dysphoria, constipation, addiction, and tolerance
or life threatening such as respiratory depression (Table 7.1).2 In this regard,
peripheral opioid receptor agonists could have an advantage in reducing array
of these troublesome side effects while maintaining analgesic efficacy. This is
the rationale behind the growing interest in developing opioid molecules with
peripherally restricted site of action which would facilitate optimization of drug
concentration at the site of injury, thereby avoiding systemic effects. The discovery
of peripheral opioid receptors is an important stepping stone for further research
in this direction. This review will focus on the location, mechanism of action of
peripheral opioid receptors, their role in production and release of endogenous
opioids and modulation of inflammatory response in the body.
Peripheral Opioid Receptors 83
OPIOID RECEPTORS
There are three main types of opioid receptors in the CNS, the µ-, δ-, and
κ-receptors (Table 7.1).2 All three receptors modulate pain and are expressed
throughout the CNS. Animal studies have established presence of μ, δ and κ
opioid receptors in nervous and non-nervous tissues outside the CNS as will be
seen in the following text.
MECHANISM OF ACTION
Opioid receptors structurally belong to the family of seven-transmembrane G
protein coupled receptors (GPCRs). Synthesis of opioid receptors occurs in the DRG
neurons and thereafter gets transported to the nerve terminals. After binding of a
specific ligand, there occurs a conformational change which allows intracellular
coupling of heterotrimeric Gi/o proteins to the C terminus of the receptor. At the
Gα subunit, GTP gets replaced by GDP and there is splitting of the trimeric G
protein complex into Gα and Gβγ subunit. These subunits later inhibit adenylyl
cyclases and cAMP production. They also interact with different ion channels in
the membrane. Ion channels are mainly regulated by direct interaction with Gβγ
subunits.4,5 All the opioid receptors act on pre- and postsynaptic Ca2+ channels
and thereby attenuate the excitability of neurons and reduce neurotransmitter
release by inhibiting Ca2+ influx, e.g. inhibition of proinflammatory mediators
like substance P and calcitonin gene-related peptide (CGRP) release from central
and peripheral terminals of primary afferent neurons.6,7 At the postsynaptic
membrane, excitation of neuron and propagation of action potential is prevented
by opioid receptors through hyperpolarization of neuronal membrane by
opening of G protein-coupled inwardly rectifying K+ (GIRK) channels.2,8 Opioid
receptor desensitization is brought about by phosphorylation of these receptors
by enzymes such as protein kinases (A and C) and GPCR kinases. This leads to an
increased affinity for intracellular arrestin molecules. Desensitization occurs by
formation of arrestin-opioid receptor complexes which results in prevention of G
protein coupling and promotes internalization via clathrin dependent pathways.
Resensitization of signal transduction occurs by recycling of opioid receptors and
their integration into the plasma membrane, whereas receptor degradation is
brought about by action of lysosomal enzymes. GPCR-associated sorting proteins
regulate lysosomal sorting and functional downregulation.9,10
Other mechanisms of action by activation of peripheral opioid receptors
suggested are suppression of tetrodotoxin-resistant Na+ channels,11 nonselective
cation currents,12 purinergic 2X receptor-mediated currents,13 as well as
transient receptor potential vanilloid (TRPV) currents via Gi/o and the cAMP/
protein kinase A pathway.12,14 In summary, opioid agonists through their action
on peripheral opioid receptors can diminish the excitability of primary afferent
neurons and block the release of proinflammatory neuropeptides from neuronal
terminals.
PERIPHERAL OPIOID RECEPTORS LOCATION

Studies have demonstrated presence of opioid receptors in bone and joint tissue
(in the synovium and periosteum),15 keratinocytes,16 immune cells,2 thinly
myelinated cutaneous nerve fibers 17 and in DRG neurons.17,18 The µ receptors
Table 7.1 Opioid receptors and ligands

Receptor and Effects Agonist Antagonist
site actions
µ systemic Analgesia, euphoria, DAMGO, morphine, CTOP, naloxone
constipation, fentanyl, endomorphins,
respiratory depression β-endorphins
Peripheral Analgesia, DiPOA, HS731/AS006, Alvimopan, naloxone
constipation, reduced loperamide, frakefamide, methiodide,
inflammation DALDA methylnaltrexone
δ systemic Analgesia, euphoria, DPDPE, SNC80, Naltrindone, ICI 174,864,
constipation, enkephalins, deltorphin, naloxone
respiratory depression β-endorphins
Peripheral Analgesia, UK-321,130 Naloxone methiodide
constipation, reduced
inflammation
κ systemic Analgesia, diuresis, U-69593, U50,488, Norbinaltrophimine
dysphoria bremazocine naloxone
dynorphin A-B
Peripheral Analgesia, reduced Asimadoline, FE200665/ Naloxone methiodide
inflammation CR845
DAMGO, _D-Ala2,N-Me-Phe4,Gly5-ol_-enkephalin; CTOP, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-
Thr-NH2; HS731, 14-O-methyloxymorphone; DALDA, Tyr-Arg-Phe-Lys-NH2; DPDPE, _D-Pen2,
D-Pen5_-enkephalin; SNC 80, 4-(_-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,
N-diethylbenzamide; ICI 174,864, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu; U-69593, N-methyl-2-
phenyl-N-_(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro_4.5_dec-8-yl_acetamide; U50,488, trans-3,
4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide.
are present in the neurons of the gut 19 where they play an important role in
regulating gut motility, secretion and pain perception. The µ receptors have also
been described in nerve fibers of dental pulp. 20
The cells of immune system expressing opioid receptors are granulocytes,
macrophages, monocytes and lymphocytes.21 These receptors are similar in
their structural as well as pharmacological characteristics as those present in the
neurons and are also encoded by the same genes.22 Binding of opioid ligands
leads to activation of the same pathways, e.g. inhibition of adenyl cyclases, Ca2+
channels, activation of kinases and transcription factors. In vitro studies have
demonstrated that opioids regulate and attune various leukocytic functions such
as chemotaxis, cell proliferation, various receptor expression and cytotoxicity.23
PLASTICITY AND REGULATION OF OPIOID RECEPTOR

Inflammation of peripheral tissue is the most important regulatory stimulus for
regulation of opioid receptor plasticity. This was shown by experiments in which
increased recruitment of δ-receptors and thereby activation of sensory neurons
was brought about by application of capsaicin or P2Y receptor agonists causing
painful paw inflammation.24,25 In vivo, peripheral δ-opioid antinociception was
enabled by local application of bradykinin or arachidonic acid.26 Most extensively
studied opioid receptor is µ-receptors and it was consistently shown to be
upregulated.27 In a study by Puehler et al. the data suggested that the peripheral
production of the proinflammatory cytokine interleukin-1 beta is a specific

inducer of kappa opioid receptor expression in the dorsal root ganglia.28 In an
experiment with complete Freund’s adjuvant-induced hind paw inflammation,
µ-receptor mRNA displayed a biphasic up-regulation (at 2 and 96 hour), whereas
mRNA for δ-receptors remained unchanged, and κ-receptor mRNA showed
a peak at 12 hour. 28,29 In parallel, µ- and κ-receptor binding was up-regulated.
This up-regulation was dependent on factors like neuronal electrical activity,29
cytokine production in the inflamed tissue,28 and was may be mediated by
cytokine-induced binding of transcription factors to opioid receptor gene
promoters.30 This shows that tissue inflammation causes differential regulation
of opioid receptor types.
Mechanical nerve injury is another stimulus known to regulate opioid
receptors in peripheral sensory neurons and it has been implicated in causing
chronic neuropathic pain. µ-receptors were shown to be down-regulated after
nerve transection and spinal nerve ligation, after partial sciatic nerve ligation
they were either decreased or increased, and after chronic constriction injury
in which loose ligatures are placed across the sciatic or saphenous nerve opioid
receptors remained unchanged or increased. All three opioid receptors were
detected using immunohistochemistry in sensory fibers co-expressing CGRP at
the chronic constriction injury site of the sciatic nerve trunk.31 Furthermore, an
up-regulation of µ- and δ-receptors was detected by Western blot at the nerve
injury site.32,33 Thus, opioid receptor expression was increased in the damaged
nerves, irrespective of changes occurring in the DRG.
ENDOGENOUS OPIOID LIGANDS

Proopiomelanocortin (POMC), Proenkephalin (PENK), and Prodynorphin
are the precursor peptides which after processing give rise to peptides beta-
endorphin (END), Met-enkephalin (ENK), and dynorphin-A (DYN), respectively.
These peptides form the endogenous ligands of opioid receptors in the body.
These peptides exhibit affinity for all three receptors in a differential manner
(Table 7.1) and do not bind exclusively to one receptor type.2
Opioid peptide expression in immune cells: Inflammation triggers mobilization of
opioid containing immunocytes to the damaged tissue.34 These cells release the
above mentioned endogenous opioid peptides, which then activate the receptors
present in the peripheral sensory neurons thereby producing analgesia.34,35
Leucocytes that contain opioid peptides are T and B lymphocytes, granulocytes,
and monocytes/macrophages.21 In the initial stages of inflammation, neutrophils
are the major opioid peptide containing leucocytes whereas in later stages,
monocytes, macrophages and lymphocytes predominate.36 Although all types
of endogenous opioid peptides are known to be released from immune cells,
END form the major type.37 Leukocytes contain and process the precursors into
functionally active opioid peptides. Positive correlation has been demonstrated
between immune cell activation and their opioid peptide content.38
Inflammation also increases the opioid peptides in DRG.39 As a result, as the
inflammatory reaction increases with migration of these varied immune cells,
there occurs a consequent augmentation of pain relief.
MIGRATION OF OPIOID PEPTIDE-PRODUCING CELLS TO

INFLAMED TISSUE AND RELEASE OF PEPTIDES
FROM IMMUNE CELLS
Migration of immune cells to the inflamed tissue not only helps in containing
pathogens but also helps in controlling pain. This is a complex process involving
various steps like cell recruitment, adhesion and extravasation. These steps are
facilitated by adhesion molecules that are upregulated on vessel endothelia
during inflammation.21
Initially, leucocytes attach to and roll along the endothelial cells mediated by
L-selectin on leucocytes and E and P selectins on endothelial cells. Subsequently,
activation of leukocytes is brought about by chemokines released from endothelial
and inflammatory cells. This results in upregulation of integrins; which by
means of intercellular adhesion molecule-1 (ICAM-1) mediate firm adhesion of
leucocytes to endothelial cells. Final step involves transmigration of leucocytes
across endothelial barrier mediated by, platelet-endothelial cell adhesion
molecule-1.40,41 Neurokinins (e.g. substance P) by upregulating adhesion
molecules on endothelium and increasing various chemokines production
through NK-1 receptors contribute to inflammation.42 Several endogenous
factors help in regulating release of these opioid peptides from immune cells
namely corticotropin-releasing factor (CRF), interleukin 1β, noradrenaline.43
Noradrenaline present in sympathetic nerve fibers in proximity to these cells
stimulated END release from leucocytes through adrenergic receptors.43
MODULATION OF PAIN AND INFLAMMATION VIA

PERIPHERAL OPIOID RECEPTORS
Inflammation is a protective immune response which follows tissue injury.
Peripheral opioid receptors are present in sensory nerves in both normal tissue
and during inflammation. However, peripheral opioid agonists producing
analgesia significantly in inflammation and insignificantly in normal conditions
suggest that analgesia is induced by inflammation. In the initial stages of
inflammation, mediators such as bradykinin, prostaglandins and chemokines are
produced which cause pain and swelling. Simultaneously there occurs secretion
of opioid peptides, somatostatin and endocannabinoids. These mediators,
released by immune cells relocated to the site of inflammation, in fact help in
reducing pain and controlling damage to peripheral tissue. These mechanisms
are based on interaction between immune and nervous systems. The goal is to
stabilize the internal milieu as soon as possible and to prevent further injury.44
Inflammation leads to upregulation of opioid receptors by facilitating all
stages; from formation to functioning of opioid receptors. It results in increased
opioid receptor mRNA synthesis;19,45 increased axonal transport as well as
increased G-protein coupling at nerve terminals.46 There occurs differential
expression of opioid receptors as per the duration of inflammation; during early
stages the effective number of opioid receptors does not increase whereas they
increase at later stages.47
Activation of the peripheral opioid receptors is brought about by endogenous
opioid peptides released from immune cells as is stated above. Stress also acts as
a stimulus for opioid peptide secretion and receptor activation.48 Machelska et
al.49 demonstrated that in early stages of inflammation, endogenous peptides are

derived from leucocytes and activate peripheral receptors to inhibit nociception.
Central mechanisms significantly compliment this at early stages. At later
stages (4 days), antinociception is exclusively the function of peripheral opioid
receptors. To summarize, peripheral mechanisms of pain control become more
prevalent with duration and severity of inflammation.21
Inflammation causes disruption of perineurium and exposes the receptors
present on nerve endings to endogenous and exogenous opioid peptides
facilitating antinociception. There is evidence supporting the observation that by
modulating the perineurial permeability efficacy of locally applied ligands can be
improved.50
Long term opioid treatment was believed to induce tolerance to the analgesic
effect, however this belief has been challenged by recent studies; which have put
forth the concept that development of tolerance can be prevented by receptor
internalization and recycling of receptor.9,27,51 the continuous availability of
endogenous opioids leads to recycling and preserves signalling of µ receptors
thereby preventing tolerance. In patients undergoing knee surgery, injection of
naloxone in the knee joint led to increased postoperative pain.52 These findings
suggest that in a stressful situation opioids are tonically released in the damaged
tissue.
Opioid peptides and receptors are expressed in immune cells, fibroblasts,
melanocytes and keratinocytes.22,27,53,54 These decrease the release of cytokines,
substance P and CGRP and hence prevent plasma extravasation and edema
formation. In addition, opioids have mitogenic properties which help in
regeneration of mucosa.55 They thus help in re-epithelization and wound
healing.54
POTENTIAL FOR CLINICAL APPLICATIONS

Opioid drugs impermeable to the blood-brain barrier can lead to a reduction in
or absence of the central nervous system side effects of respiratory depression,
sedation, tolerance, and addiction and physical dependence. Hence, there is
a tremendous clinical potential for tapping into this peripheral opioidergic
system with the help of peripherally acting opioid receptor agonists. In the last
two decades, there has been a steady stream of research dedicated to develop
peripherally restricted opioid receptor agonist molecules for this purpose.
As of date, there are no specifically approved peripherally restricted opioid
molecules available solely for peripheral analgesic application. Analgesia after
topical application of opioids has been demonstrated in patients with various
types of acute (e.g. orthopedic, dental, abdominal, urological, and eye surgery)
and chronic pain (e.g. rheumatoid and osteoarthritis, oral mucositis, complex
regional pain syndrome.38,56,57
NOVEL PERIPHERALLY RESTRICTED OPIOID AGONISTS

Peripherally restricted exogenous kappa-opioid receptor agonists: Unlike µ
receptor agonists, κ receptor agonists do not induce central nervous system
side effects or gastrointestinal transit inhibition. The first generation κ receptor
agonists included spiradoline and enadoline.58,59 These κ receptor agonists
were small molecules, orally active, and able to penetrate the brain. They lacked
side effects similar to that seen with morphine, at the same time being effective
clinically.60 Further study showed that the side effects that were seen were
sedation and euphoria, neuropsychiatric effects leading to the discontinuation of
its development any further.60
The second generation of peripheral κ receptor agonists was chemically
related to the first generation of kappa-agonists but more peripherally selective.
This generation of peripheral κ receptor agonists also composed of orally active
small molecules, a major example being EMD61753, also known as asimadoline.61
Unfortunately, the advantage of asimadoline being more peripherally restricted
than the earlier drugs was offset by its lack of analgesic efficacy at permissible
doses.61
The third generation of peripheral κ receptor agonists was based on injectable
(nonoral) peptides because of their hydrophilic property and hence relative lack
of penetration of the blood-brain barrier. Of this class of compounds, two have
shown particular promise: FE200665 and FE200666. These two compounds were
shown to be peripherally selective κ receptor agonists with analgesic and anti-
inflammatory properties.62 Though promising at the animal and preclinical levels,
κ receptor agonists need more studies at the clinical level to demonstrate their
efficacy. Their effects on gastroenterological symptoms of pain and distension,
however, have been more noteworthy, as demonstrated by CR66568 and also by
fedotozine, ADL-10-0101, and asimadoline. Fedotozine was found to be superior
to placebo in reducing abdominal pain and bloating in nonulcer dyspepsia63
and Irritable Bowel Syndrome64ADL-10-0101, was effective in reducing pain in
patients suffering from chronic pancreatitis.65
Peripherally restricted exogenous µ receptor agonists: Three broad strategies
have been pursued to demonstrate the beneficial effects of µ receptor agonists
in the control of pain peripherally. The first is the use of centrally active agonists
(the prototype being morphine) in peripheral locations for peripheral opioid
action, e.g. use of intra-articular injection of morphine into inflamed knee joints,
which has been shown to produce analgesia with efficacy similar to that of local
anesthetics or steroids without systemic or local side effects.66,67 The second is
the oral or systemic use of a µ receptor agonist that does not cross the blood-
brain barrier. The best example of this class is use of loperamide to attenuate
neuropathic pain. The third is the development of specific compounds with
peripheral and selective µ receptor agonist action. Another potent analgesic
with µ receptor effects is Frakefamide. It acts on peripheral opioid receptors and
does not cross blood brain barrier due to its large size.68 However, more work
needs to be done to assess if Frakefamide can produce analgesia comparable
with that produced by morphine in humans without the side effect of respiratory
depression.
FUTURE RESEARCH
Future research should focus not only on development of opioids with exclusive
peripheral action without any central component of action, but also with both
analgesic and anti-inflammatory action, which should boost production and
release of endogenous opioids by immune cells during inflammation, decrease
degradation and/or removal of such opioids from the site of action, thus
prolonging their effects, research should also be able to develop molecules with
action on peripheral systems that enhance the peripheral opioid system, such
as the peripheral cannabinoid receptors, chemokine system, and peripheral
adrenergic system, by utilizing gene therapy and molecular biology for better
understanding of these peripheral opioid receptors and their ligands.69 These
peripheral opioid acting drugs will also be used as an alternative as non-addicting
opioids in the future.
CONCLUSION
A lot of research has shown that the opioids have antinociceptive action not only
in the central nervous system but also in the peripheral nervous system. These
peripheral analgesic actions are modulated by action on the peripheral opioid
receptors. These actions of opioids on peripheral receptors gets enhanced
in presence of inflammation, which releases propeptide substances like
corticotropin releasing hormone and cytokines. These peripheral opioid agonists
have advantage of avoiding potential and dangerous adverse effects that usually
occurs because of action on central nervous system when these opioids are given
in systemic route, e.g. intra-articular opioids have better advantage than systemic
opioids. Substantial research work is going on to find out the effective peripherally
acting opioids, which ideally will replace systemic opioids in future and thereby
not only reduce the risk of addiction but also harmful side effects.
KEY POINTS
• Research has shown that the opioids have antinociceptive action not only in the central
nervous system but also in the peripheral nervous system.
• These peripheral analgesic actions are modulated by action on the peripheral opioid
receptors.
• The action of opioids on peripheral receptors gets enhanced in presence of
inflammation, which releases propeptide substances like corticotropin releasing
hormone and cytokines.
• Peripheral opioid agonists have advantage of avoiding potential and dangerous
adverse effects that usually occur because of action on central nervous system.
• Majority of drugs that stimulate peripheral opioid receptors are still under various
stages of developments and trials and they will replace systemic opioids in future and
thereby not only reduce the risk of addiction but also harmful side effects.
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21434585.
CHAPTER 8
Dexmedetomidine: Perioperative
Applications and Limitations
Kajal Jain, Jeetinder Makkar
INTRODUCTION
Dexmedetomidine (DEX) has emerged as a novel drug with multiple perioperative
applications in the armamentarium of an anesthesiologist. It has a highly selective
action at α-2 adrenoceptor and so possesses sympatholytic, sedative, amnestic,
and analgesic properties, notably without respiratory depression. DEX decreases
sympathetic outflow from central nervous system in a dose-dependent manner.
It potentiates the effects of anesthetic drugs and hence, is being studied intensely
as an adjunct to many anesthetic techniques.1,2 There is some evidence to suggest
its organ-protective role for kidney, heart and brain against ischemic and hypoxic
injury.3
Chemically, DEX is (+)-4-(S)-[1- (2,3-dimethylphenyl) ethyl]-1 H-imidazole
monohydrochloride. It has a molecular weight of 236.7, pH of 4.5–7.0 and a pKa
of 7.1. Although chemically similar to clonidine, DEX is eight times more specific
for α-2 adrenoceptors. It has α-2: α-1 selectivity ratio of 1620:1. Corresponding
values for clonidine are 200:1, especially for the 2a subtype.4,5 This property
renders DEX a superior sedative and analgesic than clonidine. The elimination
half-life of DEX is 2 hours versus 8 hours for clonidine whereas α half-life of
dexmedetomidine is 6 minutes. Due to short half-life, DEX can be titrated to the
desired effect and is hence useful in clinical scenarios.2 It was approved by the
Food and Drug Administration (FDA) in the United States in 1999, albeit as a
short duration sedative/analgesic (<24 hours) in the intensive care unit (ICU).6
PHYSIOLOGY
The α-2 adrenergic receptor has three α-2 isoreceptors; α-2a, α-2b and α-2c.
Amino acid composition in these three isoreceptors is 70–75% and they bind α-2
agonists and antagonists with similar affinities.7 Pharmacodynamic activity of
DEX depends on α-2 receptor subtypes. Agonism at the α-2a receptor produces
sedation, hypnosis, analgesia and sympatholysis; α-2b promotes analgesia at
spinal cord sites, causes vasoconstriction in peripheral arteries and suppresses
shivering. Action via α-2c receptor results in modulation of cognition, sensory
processing and mood and stimulant-induced locomotor activity.8
MECHANISM OF ACTION
The hypnotic and supraspinal analgesic effects of DEX result from
hyperpolarization of noradrenergic neurons in the locus coeruleus of the
brainstem. Activation of α-2 adrenergic receptor inhibits adenylyl cyclase,

enzyme catalyzing the formation of cyclic AMP (cAMP), second messenger
molecule involved in many catabolic cell processes. Decrease in amount of
cAMP in the cell favors anabolic over catabolic pathways. There is suppression
of neuronal firing with efflux of potassium through calcium-activated potassium
channels and an inhibition of calcium entry into calcium channels at the nerve
terminals.2,9,10 This suppression of inhibitory control sets off neurotransmitters
at the level of locus coeruleus, which induce hypnosis similar to normal sleep,
without causing respiratory depression, a unique feature of DEX.2,4
Analgesic effects are mediated by stimulation of dorsal horn of spinal cord,
which decreases the firing of nociceptor neurons and also inhibit the release of
their neurotransmitters.4,6 Postsynaptic activation of central α2-adrenoreceptors
produces a sympatholytic effect leading to hypotension and bradycardia.11
Owing to its diverse actions, DEX is being used for a range of clinical
applications during perioperative period. This chapter discusses the perioperative
uses of DEX, both in adult and pediatric anesthesia.
CLINICAL APPLICATONS
Perioperative Use for Improving Hemodynamics
The sympatholytic and antinociceptive properties of DEX attenuate the
hyperdynamic responses during the perioperative period. Different doses ranging
from 0.25–1 μg/kg intravenous (IV) have been studied to ameliorate the pressor
response to tracheal intubation. The optimal dose reported for attenuating pressor
response was 1 μg/kg.12,13 DEX was also advantageous in blunting extubation
response, reducing the emergence reactions and analgesic requirement in
clinical trials. Major side effects observed following the infusion are bradycardia
and hypotension.12,14 As a newer use, DEX offered better hemodynamic response
and bloodless visual field during functional endoscopic sinus surgery (FESS).15,16
A recent systematic review with five trials (254 patients) reported hemostatic
effects of DEX during FESS. DEX was more useful than inhalational anesthetics
for hypotensive anesthesia. Inhalational agents decrease blood pressure at
the expense of vasodilatation and reflex tachycardia. DEX on the other hand,
stimulates postsynaptic a-2 receptors and inhibits sympathetic activity with
decreased noradrenaline release, and hence lowers arterial pressure.17
Perioperative Analgesic
In patients undergoing surgery with general anesthesia, studies have shown that
perioperative use of DEX decreases postoperative opioid consumption, pain
intensity and nausea.18,19 Arain et al. studied 34 patients undergoing elective
inpatient surgery using DEX, with postoperative analgesia as the primary end
point. DEX group was associated with 66% reduction in the need for morphine
but was associated with slower heart rate during recovery. There was no
associated delay in discharge from recovery.11 Bolus dose of 0.8 μg/kg followed
by an infusion of DEX @ 0.4 μg/kg/hr also decreased consumption of opioid for
24 hours following laparoscopic gastric bypass.20
A systematic review and meta-analysis analyzing the effect of perioperative
systemic a-2 agonists on consumption of morphine in postoperative and pain
Dexmedetomidine: Perioperative Applications and Limitations 95
intensity reported DEX to be superior to clonidine in providing postoperative

analgesia till 48 hours postoperatively.19 Since half-life of DEX is 2 hours, it
probably offsets its analgesic efficacy on discontinuation of infusion.
DEX also showed antinausea effect, which albeit weak and short-lived could
be due to direct antiemetic properties of a-2 agonists or, due to a decrease in
requirement of anesthetics and opioids, both of which are known risk factors for
postoperative nausea vomiting (PONV) or, through a decrease in sympathetic
tone.19,21
Analgesic effects of DEX were associated with some hemodynamic effects
such as increased risk of postoperative bradycardia. This bradycardia was not
symptomatic and also did not warrant any advanced hemodynamic support.
Concomitant perioperative use of beta blockers, which may act synergistically,
increases the risk of stroke and death.22 The effect of α-2 agonists on chronic pain
or hyperalgesia requires studies addressing this issue.
Awake Fiberoptic Intubation

The use of sedatives and analgesics during awake fiberoptic intubation (AFOI) is
imperative to ease the performance of AFOI by minimizing patient discomfort.
Traditional use of GABAergic sedatives and/or opioids is associated with
respiratory depression limiting their use in patients with difficult airways.23
Several cases report use of DEX for AFOI.24,25 DEX provides anxiolysis
and sedation for patients undergoing AFOI, making them comfortable and
cooperative. Most commonly reported doses ranged between 0.3 and 0.7 μg/kg/hr
following a loading dose. One prospective randomized trial compared safety and
efficacy of DEX compared to placebo for sedating patients with high-risk airways
undergoing AFOI. Patients received DEX as a loading dose of 1 μg/kg followed
by a fixed infusion of 0.7 μg/kg/hr. Drug did not compromise airway although
some patients required midazolam to maintain Ramsay 2.26 Besides being an
anxiolytic and sedative, DEX also abolished hypertension and tachycardia due
to excessive sympathetic stimulation during AFOI. This has been attributed to
the sympatholytic effects of dexmedetomidine.27 Importantly, this drug has not
shown to be associated with respiratory depression even at higher doses.28
Finally, dexmedetomidine is associated with decreased salivary secretion.19,21
Future randomized trials examining the role of DEX for awake FOI as the sole
agent, its role as antisialagogue and optimal dosing schedule with minimal rescue
medication would be of interest during AFOI.
Adjuvant to General Anesthetics

There are some studies supporting DEX as an adjunct to general anesthesia, as
it has minimum alveolar concentration (MAC) and opiate sparing properties, by
up to 90%.2,29 DEX alters the pharmacokinetic profile of rocuronium and reduces
requirements of drug during sevoflurane anesthesia. So, requirements of muscle
relaxant and hence the risk of residual muscle weakness during emergence
decreases.30
In another study, automated administration of anesthetics showed
that DEX infusion significantly spared requirements of both propofol and
remifentanil during induction. Further requirement of propofol for maintenance
of anesthesia was reduced. No significant adverse effects (bradycardia and
prolonged recovery) were encountered. The authors opined that DEX is a useful
adjuvant as it not only reduced the anesthetic requirement but also enhanced
postoperative analgesia.31In another interesting study, intraoperative infusion
of DEX was comparable to epidural anesthesia for reduction of stress response
when combined with total intravenous anesthesia (TIVA) for abdominal surgery,
without compromising hemodynamic stability.32 The authors found it as a useful
alternative where placing epidural was risky.
Adjuvants with Locoregionals

DEX is yet to be approved by US FDA for its use in regional anesthesia. However,
it has been extensively studied as an adjuvant to both peripheral anesthesia and
neuraxial analgesia.
‘Peripheral neural blockade’: DEX has been used as an adjuvant to different local
anesthetics in different approaches to brachial plexus block. The current data
has shown that DEX extends postoperative analgesia besides improving block
characteristics and is hence, beneficial to both the patient and provider following
a single shot injection. Other than prolonging the duration of analgesia, DEX
was also found to prolong both sensory and motor block, which may offset the
advantage in case of ambulatory procedures, as it may delay discharge. A dose-
dependent effect has been demonstrated.33,34 Esmaoglu et al. added 100 μg/mL
DEX to levobupivacaine for axillary brachial plexus blockade and evaluated onset
of sensory block, motor block and duration of analgesia.33 Authors found that it
shortened sensory and motor block onset time and extended block duration.
Fritsch et al. added 150 μg DEX to ropivacaine for the interscalene brachial plexus
blockade. The median duration of nerve block reported was 18 hours longer as
compared with the plain local anesthetic (P > 0.0001).34
The effect of DEX in peripheral nerve blocks is probably not mediated by
central nervous system effects or vasoconstriction. The mechanism of action of
perineural DEX has been described at the nerve level where it acts by maintaining
a hyperpolarized state rendering the nerve inactive to generate a new action
potential. The effect is greater in unmyelinated C-fibers (pain fibers), and small
myelinated fibers instead of the large, myelinated motor fibers.35 A meta-analysis
highlighted DEX as a potential local anesthetic adjuvant that also enhanced
motor and sensory upper limb blocks, but authors lamented on the paucity of
data on safe use of perineural DEX in the clinical setting.36
Animal studies have not shown any evidence of neurotoxicity following
perineural DEX whereas human data is awaited.37 Perineural DEX may lead
to side effects, such as hypotension and bradycardia with increased dosage,
along with its effects such as sedation and anxiolysis. The clinical trials have
not studies these issues as primary end points. Esmaoglu et al. reported a high
incidence of bradycardia, despite the absence of hypotension with the use of
the drug for brachial plexus block.33 Thus, the doses of adjunctive DEX, which
achieve beneficial postoperative analgesic effects without side effects, of note,
neurotoxicity, sedation and stable hemodynamics need to be studied further.32
Some authors have suggested that use of ultrasound may allow lesser volumes
and more concentrated drug to be used, which may ultimately translate to
reduced systemic uptake and side effects.35
‘Neuraxial analgesia’: Use of neuraxial DEX with local anesthetics has been
investigated in some randomized controlled trials (RCTs). The analgesic effects
of neuraxial DEX due to inhibition of the activation of spinal microglia and

astrocyte, which decreases the release of nociceptive substances.38 Following
initial studies, a systematic review observed that doses between 3–10 μg of DEX
were studied when mixed with hyper or isobaric bupivacaine (5 or 7.5 mg/mL) or
ropivacaine (5 mg/mL). The pooled result showed that neuraxial DEX prolonged
sensory block duration (P < 0.00001). Time to first analgesic request and duration
of motor block were also increased by 70% and 87%, respectively.39 Halder et
al. suggested 3–5 μg DEX as an effective dose when mixed with bupivacaine or
ropivacaine without hemodynamic side effects.40 When 1 μg/kg DEX was used in
the epidural space, durations of sensory and motor blockade and postoperative
analgesia were enhanced. Sedation was pronounced sedation but did not result
in any adverse outcome.41
Intravenous DEX prolongs the duration of sensory block, motor block, and
time to first analgesic request associated with spinal anesthesia.42 Arzola et
al. showed that IV DEX produced a greater degree of differential blockade by
preferentially blocking myelinated A α-fibers involved in sensory conduction
over unmyelinated C fibers involved in motor conduction. A selectively prolonged
sensory analgesia may subsequently be beneficial for use in ambulatory
surgeries.43 The use of IV DEX may potentiate the local anesthetic effects along
with intraoperative sedation.
‘Intravenous regional anesthesia’: DEX has been used as an additive to the
local anesthetic during intravenous regional anesthesia during upper limb
surgeries.44 The regression of sensory and motor block times was improved and
postoperative analgesia was prolonged with the use of DEX (0.5 μg/kg). It also
allowed a clinically significant reduction in the total local anesthetic dose. There
are some animal studies, which suggest additional DEX provides protection from
local anesthetic–induced central nervous system and cardiac toxicity.45
As Novel Agent in Special Situations

‘Anesthesia for functional neurosurgery’: In order to access brain tumors in
close proximity to eloquent areas, intraoperative mapping can achieve better
outcomes. Awake craniotomy (AC) allows intraoperative mapping but this
procedure requires sedation to facilitate wakefulness during mapping. Several
case reports suggested DEX as a sedative during AC.46,47 The drug has been used
to lower the doses of sevoflurane and propofol to facilitate intraoperative wake up
tests in perioperative regimens of posterior spine fusion in pediatric population
also. Dexmedetomidine 0.1–0.3 μg/kg/hr maintains normal respiration and
tone of airway in children undergoing resection of epileptic seizure foci. This
allows awakening of child enabling the child to check for responsive to verbal
stimulation for functional brain mapping. Also the drug preserves epileptiform
activity facilitating identification of seizure activity in children with seizure
disorder.47
The optimal sedation or anesthetic technique for awake craniotomy is under
study. A randomized controlled trial tested the ability to perform intraoperative
brain mapping and the efficacy of DEX with propofol-remifentanil based
sedation in AC, for supratentorial tumor resection. DEX was associated with a
lower incidence of respiratory adverse events.48
‘Monitored anesthesia care (MAC)’: DEX given as 0.5–1.0 μg/kg is the most

studied loading doses followed by variable infusions rates (0.3–0. μg kg−1 hr−1)
These doses are tolerated well, considered safe, and effective and may serve as
an alternative to a combination of benzodiazepine and opioid. Use of DEX was
associated with a significant reduction in requirements for both midazolam and
fentanyl without clinical evidence of respiratory depression.49
‘Laparoscopic bariatric surgeries’: Morbidly obese patients are prone for
postoperative obstructive sleep apnea and ventilatory depression secondary to
use of opioid. DEX has an opioid-sparing effect and does not cause respiratory
depression, So, it has been increasingly used “off- label” during bariatric
surgery. Dex infusion, 0.2– 0.8 μg kg−1 hr−1, produced anesthetic-sparing effects,
decreased need for opioids and lower MAP values in laparoscopic bariatric
surgery patients.50
DEXMEDETOMIDINE IN PEDIATRIC ANESTHESIA

Though not fully approved for use in pediatric population, DEX has been used for
anxiolysis before surgery, adjunct medication during and after surgery, decrease
incidence of emergence agitation, shivering and pain in the postoperative period.
In addition, it has been extensively used to provide sedation for non-painful
procedures. DEX showed a relatively safe hemodynamic and pharmacological
profile, but further studies are required to establish its safety and efficacy.
Anxiolysis
DEX can be administered by buccal, intranasal and intramuscular route as
a premedicant to children. Oral route is not preferred because of limited
bioavailability of 16%. On the other hand, bioavailability using nasal and buccal
routes is 65% (35–93%) and 81.8% (72.6–92.1%), respectively.51
Intranasal use of drug is associated with greater advantages when compared
to buccal route or oral midazolam. Median time to onset of sedation using
1 μg/kg of intranasal DEX is 25 minutes with a median duration of 85 minutes. At
a higher dose, intranasal DEX 2 μg/kg produces faster onset of sedation, better
acceptance to a mask for inhalation induction, and decreased cardiovascular
variability. Use of DEX is further characterized by a fast arousal from sedation and
minimal respiratory depression. The only disadvantage of this drug is slower onset
of action and this makes the drug unsuitable substitute for oral midazolam.52
Procedural Sedation
Dexmedetomidine induces sleep activity similar to that seen in natural sleep.
The sedative characteristics are different from other sedative drugs as DEX is not
sympathomimetic. Further drug maintains spontaneous ventilation and airway
tone. This makes it an attractive option in children with symptoms of airway
obstruction.
Radiological Procedures
For magnetic resonance imaging (MRI) loading dose of 2–3 μg/kg followed by an
infusion of 2 μg/kg provided good sedation in one study. In another study, 1 μg/kg
bolus followed by an infusion of 0.5–0.7 μg/kg/hr provided adequate sedation in
children aged 1–7 years. 53,54 For computed tomography (CT) adequate sedation
can be achieved in 10min in children receiving 2–4 μg/kg of bolus dose followed
by a maintenance infusion of 1 μg/kg/hr. Coadministration of rescue DEX
with propofol has been described for sedation in children undergoing cardiac
catheterization, radiotherapy and awake craniotomy.55
Intraoperative Use
Dexmedetomidine in a dose of 1 µg/kg administered over 10 minutes maintained
sedation level within the range of the Observer’s Assessment of Alertness and
Sedation (OAA/S) scale 3–4 during dental treatments.56
Postoperative Use
Dexmedetomidine significantly reduces the incidence of emergence agitation
after sevoflurane and desflurane anesthesia.57 However, optimal dosing of
dexmedetomidine for emergence agitation has not been determined in children.
A rapid bolus may be preferred over a prolonged bolus over 10 minutes. Doses
ranging from 0.25–1 μg/kg has been reported in literature. Dexmedetomidine has
been successful to treat postoperative shivering. The exact dose and mechanism
of this effect is unknown.
CONCLUSION
Dexmedetomidine is a upcoming drug for perioperative use. The multiple effects
of DEX such as sedative, anxiolytic, analgesic and sympatholytic actions without
respiratory depression in clinically used doses has attracted the attention of several
experts. Anesthesiologists are exploring its utility potential in different settings
as an adjunctive drug to general and locoregional anesthesia. Bradycardia is a
worrisome side effect. The other shortcomings include a delay in onset to action
especially in short duration procedures and its cost-effectiveness. The drug is still
off label for use in areas specifically where neurotoxic effects need further human
and experimental data. A robust data complying with drug approval bodies and
ethics are required to authenticate its liberal use in times to come.
KEY POINTS
• D exmedetomidine, a highly selective α-2 adrenergic agonist has been used efficaciously
during perioperative period as an adjunct to general and locoregional anesthesia.
• Data has demonstrated its major benefits as analgesic, anesthetic and as an anxiolytic
in various clinical settings.
• A dose-dependent effect has been observed. An increased incidence of bradycardia is
seen with higher doses.
• Novel uses of dexmedetomidine in bariatric, functional neurosurgery and its organ
protective effects are areas of interest.
• Future research should show evidence of safety through properly conducted human
and experimental studies.
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CHAPTER 9
Pheochromocytoma:
Current Concepts and Management of
Laparoscopic Excision
Rajeshwari Subramaniam, Ajisha Aravindan
INTRODUCTION
Pheochromocytomas are tumors originating from chromaffin cells in the
sympathetic ganglia. A significant number present with dramatic, and typical
symptoms (headache, diaphoresis and palpitations). However, with the
increasing use of diagnostic imaging for screening of abdominal complaints,
more pheochromocytomas are being discovered early, or as ‘incidentalomas.
Patients with a suspicion of pheochromocytoma are best screened by plasma-
free metanephrines, which have a sensitivity approaching 100%, and normal
levels of which can reliably exclude pheochromocytoma. Current practice of
medical optimization combined with intensive perioperative monitoring and
laparoscopic approach has made the procedure safer than 50 years ago.
ANATOMY
The primitive neural crest consists of chromaffin cells, the precursors of
sympathetic and parasympathetic ganglia. These neural-crest derived organs
are termed paraganglia, which may be sympathetic or parasympathetic, and
extend from the skull base to the pelvis. Paraganglia of the adrenal medulla are
termed ‘pheochromocytoma’ (Figs 9.1A and B).1 In general, non-functional
paragangliomas are parasympathetic, whereas functional or active paragangliomas
are sympathetic.
SIGNS AND SYMPTOMS

Although the majority of pheochromocytomas are histologically benign, they
are ‘functionally’ malignant, in that they produce a vast spectrum of symptoms
related to virtually all organ systems. The predominant classic symptoms are
headache (80%; severe, pounding, global), sweating (54%) and palpitations
(67%). The classic triad of headache, diaphoresis and palpitations, seen in up to
20–40% of patients, has a high specificity (93.8%) and sensitivity (90.9%).
Headache and hypertension occur typically in predominantly norepinephrine
producing tumors, whereas palpitations, sweating, anxiety, panic or doom are
more suggestive of epinephrine or dopamine producing tumors.2-4 Hypertension,
present in >75% of patients, is paroxysmal in 48%, suggestive of epinephrine,
and/or dopamine predominance; it is sustained in 29% (usually attributed to
norepinephrine). The severity of hypertension is influenced by the amount of
Sites of paraganglioma
Cervical sympathetic chain
Posterior mediastinum
Organ of Zuckerkandl
Urinary bladder
Pelvis
A B
Figs 9.1A and B Pheochromocytoma (A) and Paraganglioma (B)
Source: Adapted from WM Manger1
circulating catecholamines and the cardiovascular response to catecholamines.

In a few patients (13%) blood pressure may be normal despite high levels
of circulating catecholamines due to receptor ‘downregulation’. Blunting of
sympathetic reflexes in these patients may lead to hypotension and shock during
unrelated surgery.5 In large tumors (>6 cm), extensive intra-tumoral metabolism
of expressed catecholamines may also result in a normotensive, asymptomatic
patient. Rarely, the patient may present with hypotension and shock-like features
(typical of pure epinephrine tumors). The classic triad of headache, diaphoresis
and palpitations, seen in up to 20–40% of hypertensive patients has a high
specificity (93.8%) and sensitivity (90.9%) for diagnosis of pheochromocytoma.6
Occasionally cardiovascular symptoms—congestive heart failure (CHF),
myocardial infarction (MI), angina or pulmonary edema may be predominant.
Pheochromocytoma should be included in the differential diagnosis of acute
coronary syndrome-like symptoms in young patients. Severe hypertension and
continued adrenoceptor activation can lead to hypertrophic cardiomyopathy
with ventricular dysfunction. This is similar to stress-induced (takotsubo)
cardiomyopathy.7 Hypertension, tachycardia and arrhythmia may occur during
diagnostic procedures (colonoscopies), induction of anesthesia, unrelated
surgery, intake of foods containing tyramine and drugs such as MAO inhibitors.
Metabolic derangements include diabetes (due to suppression of insulin
and increased hepatic glucose output), lactic acidosis, hypercalcemia (when
associated with parathyroid adenomas), diarrhea, fluid and electrolyte imbalance
(excessive production of vasoactive intestinal peptide (VIP). Tumor necrosis may
lead to shock and acute abdomen. Pheochromocytoma multisystem crisis (fever,
multiple organ failure, encephalopathy, hypertension or hypotension) needs
vigorous medical management and emergency tumor removal. Right-sided
pheochromocytomas are seen to have more ECG manifestations.8
Pheochromocytoma: Current Concepts and Management of Laparoscopic Excision 105
Table 9.1 Management plan for incidentaloma11

1 mg dexamethasone suppression test, plasma metanephrine assay
[K+], aldosterone levels; renin activity ratio in hypertensives
Surgery: Tumors >6 cm, functional adrenocortical tumors, biochemically positive
pheochromocytoma
Tumors <4 cm: monitoring with frequent metanephrine assay, MRI
PEDIATRIC PHEOCHROMOCYTOMA
In children, symptoms of pheochromocytomas are somewhat different.
Tachycardia and sustained hypertension are found in nearly 100% cases.
Cardiomyopathy is a good indicator of the duration of hypertension. Abdominal
pain, weight loss, polyuria, behavioral problems and fever form are other
symptoms unique to pediatric patients.9 Visual disturbances are seen in a large
proportion of children (60–80%). Hypertensive children warrant thorough and
urgent investigation since advanced stage malignant pheochromocytoma has a
poor prognosis.
Incidence of hereditary pheochromocytoma/paraganglioma is >50% at age
<18 years, and up to 70% in children <10 years old. These pheochromocytomas
are commonly multifocal, bilateral, or familial, and have a high preponderance of
succinate dehydrogenase subunits B (SDHB) mutation which is associated with
a higher malignancy rate than mutations in succinate dehydrogenase subunits D
(SDHD) or succinate dehydrogenase subunits C (SDHC) genes.10
A few newer genes are now being implicated in pediatric pheochromocytomas
and paragangliomas. These are:
• SDHA gene: Tumor suppressor gene, resposible for abdominal paraganglioma
• KIF1B6: Noradrenergic pheochromocytoma, ganglioneuroma, neuroblastoma
• PHD2: Erythrocytosis, abdominal paraganglioma
INCIDENTALOMAS
An adrenal mass found on routine screening is termed ‘incidentaloma’. Up to
5% adrenal incidentalomas are pheochromocytomas. Grumbach et al.11 have
outlined the management of incidentalomas (Table 9.1).
PATHOPHYSIOLOGY OF HYPERTENSION
Apart from circulating catecholamines, enhanced sympathetic nervous system
(SNS) activity is responsible for maintaining elevated blood pressure (BP) in
pheochromocytoma. Loading of sympathetic vesicles with catecholamines,
increased sympathetic neuronal impulse frequency and selective desensitization
of presynaptic a2-adrenergic receptors, result in enhanced release of neuronal
NE during nerve stimulation. Any direct or reflexly mediated stimulus to the
SNS may release excessive quantities of NE into the synaptic cleft and produce
a hypertensive crisis. The proximity of released NE to its receptor results in
severe hypertension and marked symptoms with relatively small increments in
circulating NE. This phenomenon also explains the paroxysms of hypertension
that are triggered by pain, emotional upset, intubation, anesthesia, or surgical
skin incision and explain the elevations in serum and urine catecholamines
that can occur for up to10 days after surgical resection of pheochromocytoma.
Receptor downregulation due to (a) internalization of receptors and (b) reduced
binding affinity of catecholamines to receptor ‘desensitization’ can lead to normal
BP readings despite high circulating catecholamine levels.5,8,12
GENETIC BASIS OF PHEOCHROMOCYTOMA

Germ-line mutations are found in nearly 25% of apparently sporadic
pheochromocytomas. They are of four types:
1. The retproto-oncogene (RET) mutations leading to multiple endocrine
neoplasia (MEN) type
2. The von Hippel Lindau (VHL) gene mutations leading to VHL syndrome;
bilateral adrenal pheochromocytomas may be present in up to 46% family
members of patients with VHL or MEN 2 syndrome.
3. The neurofibromatosis type I (NF1) gene is associated with von
Recklinghausen’s disease. Approximately; 5% patients with neurofibromatosis
develop pheochromocytoma.
4. Genes encoding succinate dehydrogenase subunits D (SDHD) and B
(SDHB), are associated with familial non-syndromic pheochromocytomas,
paragangliomas and a high incidence of malignancy.
A plan for genetic evaluation of patients with pheochromocytoma presenting
for surgery has been proposed by Pacak et al.13 (Flow chart 9.1).
DIAGNOSIS
Biochemical Evaluation
Catecholamine hypersecretion has to be established before localization of
pheochromocytoma. Direct assay of plasma epinephrine (E), norepinephrine
Flow chart 9.1 Plan for genetic evaluation and counseling13
Fig. 9.2 Plan for genetic evaluation and counseling13
Abbreviations: VHL, von hippel lindau; RET, retproto-oncogene; SDHB, succinate

dehydrogenase subunits B; SDHD, succinate dehydrogenase subunits D
(NE) and urinary catecholamine metabolites (vanillylmandelic acid, VMA)

suffer from both low sensitivity (episodic/inadequate secretion from small
tumors; intratumoral metabolism in large tumors resulting in low free plasma
catecholamines) and low specificity (high levels in hypertensives, patients on
labetalol).
Since pheochromocytomas may synthesize catecholamines up to 27 times the
normal adrenal medulla, these large quantities of E and NE get metabolized in the
tumor cytoplasm by catechol-o-methyl transferase (COMT) to metanephrines,
which are continually released into the plasma. Thus metanephrines remain
elevated even if their precursors are not detectable for reasons mentioned above.
Metanephrine screening has a sensitivity of 97–99% for sporadic and small
familial tumors/incidentalomas. This high sensitivity makes it the test of first
choice to be carried out in patients with clinical symptoms but normal plasma
catecholamines. However, the specificity is lower (85–89%), especially in patients
>60 years.
High plasma normetanephrine to norepinephrine, or metanephrine to
epinephrine ratios are strongly predictive of pheochromocytoma. If catecholamine
and metanephrine levels are borderline, a clonidine suppression or glucagon
stimulation can exclude or confirm the presence of pheochromocytoma.
Lenders14 has outlined the sensitivity and specificity of various biochemical
tests for pheochromocytoma (Table 9.2).
Anatomic and Functional Localization4,15,16

Localization should be initiated after unequivocal biochemical evidence of a
pheochromocytoma. An algorithm for localization is provided in Flow chart 9.2.
Imaging modalities can be grouped into:
• Anatomic: CT, MRI
• Functional: Scintigraphy employing meta iodo benzyl guanidine (MIBG) or
position emission tomography (PET).
Computerized tomography (CT) has 93–100% sensitivity for detecting adrenal
tumors from 0.5 to 1 cm, and 90% for detecting extra-adrenal tumors. Sensitivity
of CT increases by enhancement. It is important to protect the patient with alpha
and beta-blockers prior to the procedure. Magnetic resonance imaging (MRI) is
marginally more sensitive than CT and has other advantages. T2-weighted MRI
with gadolinium enhancement can be used in the pregnant patient, in children
and patients allergic to radiocontrast agent.
Table 9.2 Biochemical testing for pheochromocytoma1

Parameter Sensitivity Specificity
Plasma-free metanephrines 99% 89%
Plasma catecholamines 84% 81%
Urinary catecholamines 86% 88%
Urinary fractionated metanephrines 97% 69%
Urinary total metanephrines 77% 93%
Vanillylmandelic acid (VMA) 64% 95%
Flow chart 9.2 Localization of pheochromocytoma
Modified from Reference 16.
MIBG scans can detect recurrent/metastatic pheochromocytomas, extra-

adrenal tumors, tumors with fibrosis/distorted anatomy, or in unusual locations.
The specificity of MIBG is 95–100%. Labetalol and tricyclic antidepressants can
give rise to false negatives as they prevent uptake of MIBG at sympathomedullary
tissue. These should be withdrawn for 5 half lives. 123I-MIBG has superior imaging
qualities to 131I MIBG but a very short half-life.
PREOPERATIVE PREPARATION
Preoperative pharmacological preparation has reduced perioperative mortality of
pheochromocytoma to less than 3%. The benefits of preparation are summarized
in Flow chart 9.3.
Alpha Blockers
Phenoxybenzamine, a non-selective, long-acting alpha-blocker, is administered
orally 10 mg bid, and increased up to 1 mg/kg/day; using intravenous (IV) route,
alpha block can be achieved by 0.5 mg/kg/day over 5 h, for 3 days. Adequacy of
treatment is apparent in 2–3 weeks. Significant orthostatic hypotension, nasal
stuffiness, excessive somnolence and peripheral edema can lead to patient
noncompliance. Reflex tachycardia is common due to blocking of presynaptic
receptors causing enhanced availability of NE, which acts on Beta-1 receptors.17,18
Doxazosin, prazosin and terazosin are selective alpha-1 antagonists. The first
dose may produce profound hypotension due to uninhibited NE reuptake
combined with inhibition of NE at postsynaptic alpha-1 receptors and should be
Flow chart 9.3 Benefits of preoperative preparation
given at bed time with overnight IV hydration. Selective a-1 blockers lack reflex
tachycardia. Doxazosin is administered as a single dose (1–16 mg19); prazosin
and terazosin are administered 4–6 hourly. Although proponents of doxazosin
argue for its stable hemodynamic profile, its prolonged duration of action leads
to higher incidence of postoperative hypotension.20
The hematocrit offers a good guide for preoperative alpha-blockade. It is
not uncommon for the hematocrit to drop by 10–15% during the course of the
treatment. Patient well-being and a significant reduction in symptoms are also
seen with adequate therapy. It is not unusual for ECG changes to regress after
several weeks of alpha-blockade. The average duration of preoperative alpha
blockade is 10–14 days. A longer duration of blockade may be needed to optimize
myocardial function.
Beta Blockers
Beta blockers are specifically indicated (a) for tachycardia consequent to a
blockade and (b) to control supraventricular and ventricular arrhythmias. beta-
blockade initiated prior to a blockade, can cause unopposed a- action and severe
hypertension.21 For this reason, labetalol is not suitable as a primary drug because
beta-blockade exceeds alpha-blockade capability (1:7). Labetalol also prevents
uptake of 131I MIBG and interferes with imaging. It should be stopped at least 2
weeks before MIBG. The preferred beta blockers are the cardioselective agents
atenolol (25–50 mg) and metoprolol (50 mg).
Calcium Channel Blockers

Amlodipine 10–20 mg/day, nicardipine 30–90 mg/day or verapamil 180–240
mg/day are recommended for the apparently normotensive patient, those
with occasional paroxysms of hypertension and in patients with secondary
cardiovascular complications. These drugs inhibit NE-induced intracellular
calcium influx and prevent catecholamine-induced coronary spasm, myocarditis,
and attenuate hypertensive responses to noxious stimuli.
Alpha-methyl-para Tyrosine
Alpha-methyl-para throsine (α–MPT) interrupts catecholamine synthesis.
Pretreatment for 3 days depletes tumor catecholamine stores by 50%. There
is a good correlation between perioperative cardiovascular instability and

catecholamine release from pheochromocytoma. MPT is especially useful
in extensive metastatic disease to control refractory blood pressure or where
tachycardia of a blockade (CAD) or beta blockade (LV dysfunction) may not be
tolerated.22 The dose is 250 mg orally, increased by 250–500 mg/day to reach
1.5–2 g/day for 1–3 weeks.
Combined Medical Blockade (MPT Combined with Alpha-Blockade)

This combination has been reported to facilitate perioperative BP control and
reduce intraoperative hemodynamic instability. Numerous side effects of MPT
lead to poor compliance: diarrhea, crystalluria, depression, galactorrhea, anxiety
and extrapyramidal symptoms requiring carbidopa.
An intake of 2–3 L of saline in alpha-blocked patients decreases the severity of
orthostatic hypotension and post-excision hypotension. Adequacy of preoperative
preparation is assessed using Roizen’s criteria:
• BP <160/80 mm/Hg.
• Orthostatic hypotension not less than 80/60 mm/Hg.
• No more than 1 VPC in 5 min
• No new ST-T changes on the ECG over the last week.
Other goals of preoperative preparation23 are:
• To assess myocardial function
• To correct hyperglycemia/electrolyte abnormalities
• Patient explanation and reassurance
Cardiovascular Evaluation
A baseline ECG may reveal ischemia, LV hypertrophy and/or strain. An
echocardiogram is valuable in detecting ventricular dysfunction, evaluating
improvement with therapy, diagnosing dilated cardiomyopathy and timing
of surgery. Tissue Doppler ECHO (TDE) has demonstrated depressed systolic
strain rate (SSR) in patients with pheochromocytoma. An SSR of <2/sec. is
associated with high central venous pressure and increased risk of perioperative
cardiovascular collapse.24
With the availability of rapid, short-acting vasodilators (MgSO4, urapidil
25,26 and beta-blockers (esmolol), and potent narcotics (remifentanil27) and
dexmedetomidine, conventional preoperative preparation protocols are being

questioned. Boutros et al.28, Ulchaker et al.29 and Poopalalingam30 have published
series of patients who were rapidly prepared preoperatively using urapidil,
magnesium sulphate and labetalol. Further, Witteles31 and Emerson32 have
described outpatient preparation, which reduces the burden on hospitals. More
recently, Lentschener et al.33 question whether better knowledge of the disease,
efficiency of available intravenous short-acting vasoactive drugs, and careful
intraoperative handling of the tumor, refined anesthetic techniques would make
it possible to omit preoperative preparation in most patients scheduled for
pheochromocytoma removal.
SURGERY FOR PHEOCHROMOCYTOMA

Surgery for pheochromocytoma, once associated with a mortality of nearly
25%34 (Fig. 9.2), has now been rendered safe due to good understanding of
catecholamine physiology and vasoactive drug used, combined with invasive
hemodynamic monitoring. Improved morbidity figures started appearing from
1964 with Goldfein’s series,35 who used preoperative preparation, invasive
monitoring, epidural analgesia and painstakingly recorded hemodynamic
changes (Fig. 9.3). Pheochromocytoma management has never looked back
since.
With the advent of laparoscopic adrenalectomy for pheochromocytoma,
most intraoperative morbidity, especially related to gland manipulation, has
virtually been eliminated. Understanding catecholamine physiology, need of
vasodilators, good analgesia and volume management are fundamental to good
management of laparoscopy. Laparoscopic technique does not do away with
invasive monitoring, alertness on the part of the anesthesiologist or titration of
anesthetic depth and/or vasodilators. It imposes an extra burden of monitoring
changes related to pneumoperitoneum, but the overall reduced morbidity
is worth the effort. In this context, it is worth mentioning that a well-prepared
Fig. 9.2 Case record from APGAR34

Fig. 9.3 Case record from Goldfein35
patient requires lesser vasodilators than the one who is having blood pressure
surges all the time; consequently, vasopressors are tapered off earlier, with better
recovery of blood pressure and lesser postoperative vasopressor use. Thus, one
can trace a link between dose and timing of alpha blockade, surgical expertise
and good recovery.
Laparoscopic approach to adrenalectomy was first reported by Gagner in
1992, in a series of 3 patients.36 Two of these had Cushing’s syndrome and disease
respectively; the third was a patient with pheochromocytoma. Five years later, a
series of 100 cases of laparoscopic adrenalectomy,37 which included 25 cases of
pheochromocytoma, was published. This has been followed by numerous other
series testifying to not only the safety but also the positive advantages of this
technique over open adrenalectomy. Apart from minor advantages in the form of
better cosmesis, less pain and early ambulation, significant advantages include
decreased intraoperative hemodynamic fluctuations and blood loss.38,39
Laparoscopic procedures, employing CO2 pneumoperitoneum, are known
to be associated with several hemodynamic and respiratory consequences.
These include hypertension, tachycardia, increase in SVR, PVR, changes in
cardiac output, hypercarbia and respiratory acidosis. Humoral changes in the
form of increased catecholamines, vasopressin and cortisol levels have also
been reported. Earlier series on laparoscopic pheochromocytoma reported a
relationship of hypertensive surges with initiation of pneumoretroperitoneum,
and intra–abdominal pressures (Table 9.3).
Successful management of laparoscopic excision of pheochromocytoma thus
involves careful understanding of the possible effects of pneumoperitoneum on
Table 9.3 Series of laparoscopic pheochromocytoma

Author/route Number Insufflation Manipulation
Gagner (1996, T) 23 - ++
F Cruz (1996, T) 8 + +
Mann (1996, T) 2 ++ +++
Joris (1999, T) 8 ++ ++
Inabnet (2000, T) 11 + +
Subramaniam (2000, R) 11 + ++
Janetschek (2001, T) 24 ++ ++
Atallah (2001, R) 7 ++ ++
Tauzin-Fin (2004, T) 16 + +++
catecholamine response during various stages of surgical management. Initial

work up, pharmacological testing and localization are as for open procedure.
Anesthetic management begins with a thorough preoperative evaluation and
optimization of blood pressure, volume status, glycemic control and alleviation
of symptoms.
Preoperative Explanation and Premedication

It is imperative to visit the patient multiple times during pharmacological
optimization for the following reasons:
• Patient recognizes you as primary caregiver
• Confidence and familiarity reduce anxiety
• Ensure compliance
• Enable assessment of effect of treatment
• Appropriate modification
There is no substitute for these repeated preoperative visits. Patient is
explained about the need for, and the technique of invasive vascular cannulation
prior to induction of anesthesia. All adult patients by this time are very compliant
and comfortable with all explanations and it is the author’s personal experience
of more than 110 cases (Figs 9.4A and B).
Premedication
Oral benzodiazepines and H2 receptor antagonist are suitable premedicants.
Metoclopramide can precipitate hypertensive crisis and should be avoided.
Short-acting selective α-1 adrenergic blockers should be administered in the
morning to continue α blockade during the procedure. If the patient is on long-
acting α-1 adrenergic blockers (phenoxybenzamine/doxazosin), they should be
stopped 12–24 hours before.
OT Preparation
Anesthetic management of laparoscopic pheochromocytoma excision warrants
all preparation done for open surgery. This is because the rapidity and enormity
of BP surges may frequently be severe, as the response of each tumor is unique.
B
Figs 9.4A and B Patient pointing to proposed sites of cannulation!
Intraoperative hypertensive crises occur during:

• Stimuli like intubation and positioning
• Pneumoperitoneum
• Handling of the gland
• Squeezing the gland against the diaphragm to control bleeding
Establishing invasive arterial and central venous monitoring before induction
helps prompt detection and rapid correction by infusion of vasodilators into the
central circulation.
SNP infusion (0.01%), labetalol (5 mg/mL), magnesium sulphate (1.5–2 mg/
kg), noradrenaline infusion (80 µg/mL) are set up for all procedures.
Hypotension frequently occurs after adrenal vein ligation, and management
is aided by CVP. After patient positioning it is virtually impossible to insert a
central line. The ‘minimally’ invasive nature of laparoscopic pheochromocytoma
excision is minimal only with respect to the size of the incisions!
Invasive vascular access is, therefore, best obtained prior to induction.

Adequate preoperative explanation, topical EMLA application and a small dose
of IV midazolam (1 mg) and fentanyl (50 µg) facilitate arterial and central line
placement, the latter guided by ultrasound, with minimal patient discomfort
and good acceptance (Figs 9.5A to C). Propofol, fentanyl and vecuronium are
very satisfactory agents for induction and provide good hemodynamic stability
and intubating conditions. Magnesium sulfate (MgSO4) (1.5–2.0 g IV) prior to
C
Figs 9.5A to C Preinduction invasive vascular access in the patient. The monitor shows
hemodynamic stability
Fig. 9.6 Lateral positioning
induction pre-empts intubation response in virtually all patients, especially

in pediatrics and in extra-adrenal paragangliomas. Intubation is performed
expeditiously under adequate depth of inhalational anesthesia (isoflurane or
sevoflurane).40
Laparoscopic pheochromocytoma excision can be performed through
supine transperitoneal, lateral transperitoneal, lateral retroperitoneoscopic and
posterior retroperitoneoscopic/lumbotomy approaches. Each has its own set of
advantages/disadvantages. The supine route is preferred in cases of suspicion of
malignancy or multiple tumors where the abdomen and contralateral adrenal
can be examined in the same sitting. It is easy to convert to open procedure in this
position. For lateral transperitoneal or retroperitoneal approaches, the patient is
kept on the side and a roll is placed under the dependent costal margin (Fig. 9.6).
The lateral transperitoneal route is used in most instances. Up to four
ports are inserted. Pneumoperitoneum up to 12–15 cm H2O is employed.
Hypercarbia, catecholamine release and hypertensive crises are directly related
to the carboperitoneum pressures.41 These can be controlled effectively by small
boluses of SNP.
The main advantages of the laparoscopic approach for pheochromocytoma
are evident after the surgeon has mastered the learning curve. One of these is
minimal blood loss owing to increased magnification and accurate hemostasis.
From the anesthetic management point of view, the most significant advantage is
the decreased amplitude of hypertensive surges during gland manipulation. Two
explanations are put forward for this finding:
i. As the tissue attaching the tumor to surrounding structures is dissected
and devascularized, the patient is ‘dissected away’ from the tumor, with
consequent minimal actual handling of the tumor.
ii. The gland is handled with delicate instruments.
For intraoperative hemodynamic crises, if predominantly hypertensive
surges, treatment is with SNP 0.01% solution (titrated to effect). If the disturbance
is predominantly dysrhythmias/tachycardia, esmolol bolus (0.5 mg/kg)/

infusion can be given. With progressive vascular disconnection, both the
frequency and severity of hypertensive surges decrease. Generally, hypotension
at the conclusion of surgery is minimal, easily controlled with small doses of
noradrenaline, and can be tapered off within 6–8 hours. Pressor support is best
provided with norepinephrine which mimics the preoperative condition, till the
downregulated adrenoceptors regain their sensitivity. Care should be taken not
to attempt to treat hypotension with excessive fluids.42
It is not uncommon, in cases of bilateral pheochromocytoma, for the surgeon
to complete one side, have the patient again positioned for the contralateral
gland. Smooth intraoperative course is directly dependent on the expertise
of the surgeon. It is recommended that, patient be monitored in an HDU to
detect and treat postoperative hypotension and hypoglycemia. Small doses of
hydrocortisone (25–50 mg) may be required for 2–3 days in cases of bilateral
adrenalectomy.
Analgesia After Laparoscopic Adrenalectomy

Multimodal analgesia with port-site infiltration, paracetamol and/or NSAIDs is
usually sufficient. Neuraxial analgesia can be planned if there is a high likelihood
of conversion. Single shot intrathecal morphine (100–300 g) has been extremely
effective, in the author’s personal experience of more than 50 cases. Patients
can be ambulated the same evening. Light oral intake can be allowed 4–6 hours
postoperatively.
Pheochromocytoma during Pregnancy

Pregnancy may be complicated by pheochromocytoma. Epigastric pain,
hyperemesis, headache, hypertension may mimic pre-eclampsia. Administration
of methyldopa might precipitate hypertensive crisis. Management depends
upon the viability of the fetus. If the pregnancy is less than 24 weeks, after a
2-week preparation, laparoscopic excision has been successfully performed.43 If
near term, patient undergoes a careful cesarean section under anesthesia with
invasive monitoring, and the pheochromocytoma resected subsequently.44,45 A
scheme for management of pheochromocytoma during pregnancy is provided
in Flow chart 9.4.
CONCLUSION
Anesthesia for surgical management of pheochromocytoma, although safer than
two to three decades ago, still continues to be challenging, with unpredictable,
frequent high surges of blood pressure, possibility of significant vascular injury,
blood loss and often severe postoperative hypotension. Hypertensive crises
may occur in response to preoperative anxiety, tracheal intubation, positioning
and/or tumor manipulation with suboptimal preoperative preparation and
inadequately titrated anesthetic depth. Further, pheochromocytoma may present
as hypertensive crisis for the first time during unrelated surgery, endoscopic
procedure or administration of beta blockade alone for hypertension. A high
index of suspicion, treating severe hypertension with magnesium sulphate
and/or calcium channel blockers and always keeping pheochromocytoma as a
Flow chart 9.4 Management of pheochromocytoma during pregnancy45
differential diagnosis for a variety—cardiac, neurological or metabolic crisis—

will go a long way in safe outcome for these patients.
KEY POINTS
• P heochromocytomas are catecholamine-producing tumors arising from the adrenal
medulla. Chromaffin tumors in other parts of the sympathetic chain are termed as
‘paragangliomas’, which may or may not be functional.
• A significant number of patients present with classic triad of headache, sweating
and palpitations; however, many pheochromocytomas are being discovered during
evaluation of other conditions and as part of genetic testing.
• Preoperative alpha blockade, although debated, still remains the cornerstone of
contemporary management. It reduces symptoms and stabilizes the cardiovascular
system.
• Pheochromocytomas are increasingly being operated upon by laparoscopic technique,
for which they are eminently suited. However, in spite of smaller incisions, hemodynamic
fluctuations are expected intraoperatively, so invasive monitoring and intensive care
facilities should be available.
• Postoperatively, these patients should be monitored for hypotension, residual
hypertension, and hypoglycemia.
• Pediatric pheochromocytomas have a strong genetic predilection and are often part
of genetic syndromes, and all siblings should undergo screening for MEN IIa and b,
hereditary paraganglioma, von-Hippel-Lindau syndrome and von Recklinghausen
syndrome.
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Analg. 2004;99:680-6.
27. Dimitriou V, Chantzi C, Zogogiannis I, Atsalakis J, Stranomiti J, Varveri M, Malefaki A.
Remifentanil preventing hemodynamic changes during laparoscopic adrenalectomy
for pheochromocytoma. Middle East J Anaesthesiol. 2006;18(5):947-54.
28. Boutros AR, Bravo EL, Zanettin G, Straffon RA. Perioperative management of 63
patients with pheochromocytoma. Cleve Clin J Med.1990;57:613-7.
29. Ulchaker JC, Goldfarb DA, Bravo EL, Novick AC. Succesful outcomes of
pheochromocytoma surgery in the modern era. J Urol. 1999;161:764-7.
30. Poopalalingam R, Chin EY. Rapid preparation of a patient with pheochromocytoma
with labetalol and magnesium sulfate. Can J Anaesth. 2001;48:876-80.
31. Witteles RM, Kaplan EL, Roizen MF. Safe and cost-effective preoperative preparation of
patients with pheochromocytoma. Anesth Analg. 2000;91:302-4.
32. Emerson CE, Rainbird A. Use of a `hospital-at-home’ service for patient optimization
before resection of phaeochromocytoma. Br J Anaesth. 2003;90:380-2.
33. Lentschener C, Gajoux S, Tesniere A, Dousset B. Point of controversy: perioperative
care of patients undergoing pheochromocytoma removal—time for a reappraisal? Eur
Endocrin. 2011;165:365-73.
34. Apgar V, Papper EM. Pheochromocytoma: Anesthetic management during surgical
treatment. AMA. Archives of Surgery. 1951;62:634-48.
35. Goldfien A. Pheochromocytoma: Diagnosis and anesthetic and surgical management.
36. Gagner M, Lacroix A, Bolte E. Laparoscopic adrenalectomy in Cushing’s syndrome and
pheochromocytoma. N Engl J Med. 1992;327:1033.
37. Gagner M, Pomp A, Heniford BT, Pharand D, Lacroix A. Laparoscopic adrenalectomy:
lessons learnt from 100 cases. Ann, Surg. 1997;226:238-47.
38. Fernandez-Cruz L, Taura P, Saenz A etal. Laparoscopic approach to
pheochromocytoma: Hemodynamic changes and catecholamine secretion.World J
Surg. 1996;20:762-8.
39. Subramaniam R, Pandit B, Sadhasivam S, Sridevi KB, Kaul HL. Retroperitoneoscopic
excision of phaeochromocytoma-Haemodynamic effects, complications and outcome.
Anaesth Intensive Care. 2000;28:49-53.
40. Khetarpal M, Kulkarni D, Gambhir R, Rao SM. The effective use of sevoflurane during
resection of phaeochromocytoma. Ind J Anaesth. 2005;49:137-9.
41. Sood J, Jayaraman L, Kumra VP, Chowbey PK. Laparoscopic approach to
pheochromocytoma: is a lower intra-abdominal pressure helpful? Anesth Analg.
2006;102:637–41.
42. Iijima T, Takago T, Iwao Y. An increased circulating blood volume does not prevent
hypotension after pheochromocytoma resection. Can J Anesth. 2004;51(3):212-5.
43. Kim PTW, Kreisman SH, Vaughn R, Panton ONM. Laparoscopic adrenalectomy for
pheochromocytoma in pregnancy. J Can Chir. 2006;49:62-3.
44. Dugas G, Fuller J, Singh S, Watson J. Pheochromocytoma and pregnancy: a case report
and review of anesthetic management. Can J Anesth. 2004;51:134-8.
45. Oliva R, Angelos P, Kaplan E, Bakris G. Pheochromocytoma in pregnancy—A case
series and review. Hypertension. 2010;55:600-6.
CHAPTER 10
Perioperative Anaphylaxis
Pradeep Bhatia
INTRODUCTION
The European Academy of Allergy and Clinical Immunology has defined
anaphylaxis as a severe, potentially life-threatening systemic hypersensitivity
reaction.1 The estimated incidence of perioperative anaphylaxis is 1 in 10,000–
20,000 anesthetic procedures,2 with the overall mortality due to anaphylaxis
being less than 0.001%. It is difficult to identify the causative agent because
several drugs are administered in the perioperative period; hence, it requires
the careful analysis of clinical presentation, and of the time gap between the
administration of drug that might have been responsible and the beginning of
the reaction.
PATHOPHYSIOLOGY
Anaphylaxis can be caused by immunological mechanisms (IgE-mediated
or non-IgE-mediated), nonimmunological mechanisms, or be idiopathic.
IgE-mediated anaphylaxis is caused by the cross-linking of IgE resulting in
degranulation of mast cells and basophils. It results in the release of mediators
like histamine, prostaglandins, proteoglycans, and cytokines. Approximately
60–70% of the perioperative anaphylaxis cases are IgE mediated.3 Non-IgE-
mediated allergic reaction is because of IgG or immune complex complement-
mediated pathways.4-6 The nonimmunological anaphylaxis is due to direct
stimulation of mast cells by the causative agent (e.g. drugs) resulting in the mast
cells degranulation and release of histamine and other mediators. It is generally
transient and may present with cutaneous signs only. Idiopathic anaphylaxis is
labeled when specific allergen cannot be identified, and the serum specific IgE
levels are normal. Anaphylaxis generally occurs on re-exposure to a specific
antigen, but can also occur on first exposure, because there may be cross-
reactivity among many drugs.
RISK FACTORS
A detailed history and past medical records can reveal important factors, which
could be associated with perioperative anaphylaxis. Following patients are at
increased risk:2,3
• Patients with history of signs and symptoms, suggestive of allergic reactions
during previous surgery.
• Patients with known allergy to one of the drugs, or products, likely to be used
during the current surgery.
• Patients who have undergone several operations, particularly children with
spina bifida, due to the frequent exposure to latex.
• Patients with history of signs and symptoms suggestive of latex allergy.
• Patients with history of allergic manifestations after ingesting avocado, kiwi,
banana, pineapple, papaya, chestnut, passion fruit, or buckwheat, due to the
possibility of cross-reactivity between these foods and latex.
PERIOPERATIVE TRIGGERS
A small quantity of allergen is sufficient to cause anaphylaxis. In the perioperative
setting, the common agents involved in IgE-mediated anaphylaxis are antibiotics,
latex and neuromuscular blocking agents (NMBAs), and less commonly, colloids,
hypnotic agents, opioids, dyes, and chlorhexidine.3,7-10
The non-IgE-mediated anaphylaxis may be associated with drugs, such
as nonsteroidal anti-inflammatory drugs (NSAIDs) and iodinated contrast
agents, although these agents can also induce IgE-mediated reactions.11-14 The
nonimmunological anaphylaxis may be associated with drugs, such as opioids,
vancomycin, and NMBAs (e.g. atracurium). Other triggers of perioperative
anaphylaxis include heparin, protamine, oxytocin15 local anesthetics16,17 and
blood transfusion, including exposure to immunoglobulin A (IgA) in blood
products in patients with severe IgA deficiency.
The common sources of latex exposure in the perioperative period are those
items that have prolonged contact with skin or mucosal surfaces, such as gloves,
drains and catheters. Latex allergy is seen more commonly in patients with
repeated exposure to latex gloves or catheters from prior surgeries, especially
children with spina bifida.
The NMBAs most commonly associated with anaphylaxis are rocuronium
and suxamethonium. Cross-reactivity with other nondepolarizing NMBAs is
also highest with rocuronium and suxamethonium. In a study, patients with
anaphylaxis to rocuronium had cross-reactivity rates of 44% with suxamethonium,
40% with vecuronium, 20% with atracurium, and 5% with cisatracurium. Cross-
reactivity rates in patients with anaphylaxis to suxamethonium were 24% with
rocuronium, 12% with vecuronium, and 6% with atracurium.18
Colloids and plasma expanders, such as dextran or hydroxyethyl starch (HES),
were found to cause about 3% cases of perioperative anaphylaxis.8,19 In addition,
gelatin and succinylated gelatins in plasma volume expanders (e.g. Hemaccel,
Gelofusin) can also result in IgE-mediated anaphylactic reactions.20,21 Albumin
has also been reported to cause perioperative anaphylactic reactions.22,23
Data from American studies in 2011 and 2015, show that the most common
identifiable cause of perioperative anaphylaxis was antibiotics (58%) followed
by NMBAs (11.1–23%) and latex (17%). The antibiotics included cefazolin (60%),
penicillin (20%), cefuroxime (10%), and metronidazole (10%).24-26 The findings
were similar to a study from Spain, in which antibiotics were found to be the
most frequent cause, followed by NMBAs.27 A Brazilian study that evaluated 51
patients, reported Latex (22%) and NMBAs (6%) as the main agents responsible
for perioperative anaphylaxis.28 The clinical diagnosis and management of
anaphylaxis is same irrespective of the underlying cause.
Perioperative Anaphylaxis 123
CLINICAL FEATURES
Grading of anaphylactic symptoms according to severity of symptoms were first
proposed by Ring and Messmer in 1977.29 The modification by Mertes et al. is as
follows:8
Grades of Severity of Immediate Hypersensitivity Reactions

Grade Symptoms
I Generalized cutaneous signs: erythema, urticaria, with or without
angioedema
II Moderate multiorgan involvement with cutaneous signs, hypotension
and tachycardia, bronchial hyper-reactivity, cough, difficulty in breathing.
III Severe life-threatening multiorgan involvement: cardiovascular collapse,
tachycardia or bradycardia, arrhythmias, bronchospasm. Cutaneous signs
may be present or occur only after the arterial blood pressure recovers
IV Cardiac and/or respiratory arrest
The most common presentation of perioperative anaphylaxis include
acute-onset generalized mucocutaneous signs, respiratory manifestations,
and cardiovascular instability. A survey on perioperative anaphylaxis revealed
that cardiovascular symptoms (73.6%), cutaneous symptoms (69.6%), and
bronchospasm (44.2%) were the most common clinical features.30 Studies show
that symptoms due to IgE-mediated anaphylaxis are more severe than non-IgE
mediated ones.3,7 Skin manifestations are common in both types of anaphylaxis
but their absence does not exclude the diagnosis.8 Symptoms like gastrointestinal
manifestations (nausea, vomiting, diarrhea), hoarseness, dysphagia, dizziness,
and blurred vision are not reported by an anesthetized or a sedated patient.
Laryngeal angioedema, bronchospasm and cardiovascular collapse are the main
manifestations of anaphylaxis in the perioperative period in an anesthetized
patient.
DIAGNOSIS
Anaphylaxis is a clinical diagnosis and laboratory tests are of no use in diagnosing
anaphylaxis at the time of manifestations because they take time to process and
are prone to false negatives and positives.31 Clinical manifestations show different
severity in different patients, ranging from mild hypersensitivity reactions to
severe anaphylactic shock and death.32,33 In mild cases with single symptom,
spontaneous recovery can occur and might go un-noticed. However, the patient
will be at a higher risk of anaphylaxis in future surgery during re-exposure to
the involved agent. Diagnosing severe anaphylaxis in the perioperative period
can be difficult because hypotension, difficulty in ventilation and heart rate
variation may also arise from anesthetic agents, sympathectomy associated with
spinal/epidural anesthesia, surgical, or patient-related factors. Intraoperatively
patients are covered with drapes and generally sedated or anesthetized and
unable to report pruritus, so the early cutaneous signs of anaphylaxis might
remain un-noticed. Anaphylaxis should be suspected, if there is unexplained
hypotension refractory to vasopressors, or unexplained resistance to ventilation
and bronchospasm. Early diagnosis of anaphylaxis is very important for the
patient prognosis. Since anaphylaxis is uncommon, there may be delay in the
diagnosis by anesthesiologist in the perioperative period and the management

training on a full-scale anesthesia simulator is suggested. In a study, none of 42
anesthesiologists tested on a simulator could make the correct diagnosis during
the first 10 minutes of anaphylaxis, and most of them failed to have a structured
plan for its treatment.34
The manifestations of perioperative anaphylaxis usually occur within
seconds or a few minutes of the exposure of the causative agent, e.g. after
intravenous injection of NMBAs or an antibiotic. If the signs appear late
during the anesthesia maintenance, it suggests latex allergy, allergy to colloids,
antiseptics (chlorhexidine) or dyes. This could be due to delayed absorption from
skin or mucosa, drugs administration at the end of the surgery, or deflation of a
tourniquet resulting in the release of allergen in the circulation.4,10 Latex allergy
should also be suspected during gynecological procedures as particles from
obstetricians’ gloves may accumulate in the uterus during the procedure and can
be released into the systemic blood on injection of oxytocin.35 Patients on beta-
blockers do not present the same heart rate increase that is observed in other
patients and are at risk of late diagnosis of anaphylaxis.36
DIFFERENTIAL DIAGNOSES
Perioperative anaphylaxis should be differentiated from exacerbation of asthma,
tension pneumothorax, myocardial ischemia/infarction, pulmonary embolism/
edema, pericardial tamponade, C1 esterase deficiency, mastocytosis and clonal
mast cell disorders. Hereditary angioedema, caused by C1 inhibitor deficiency,
is a rare autosomal dominant condition that resembles anaphylaxis. The disease
manifests with angioedema of the face, larynx, oropharynx, extremities, abdomen,
and genitalia, and its common triggers include surgery, intubation, and anesthesia.
Sole angioedema is an uncommon feature of perioperative anaphylaxis,8 and the
possibility of hereditary angioedema or angiotensin-converting enzyme inhibitor
(or angiotensin receptor blocker)-induced angioedema should be considered.
INVESTIGATIONS
Arterial blood gas, renal and liver function tests should be done to detect
hypoperfusion-induced injuries.
Tryptase
Measurement of serum tryptase, a protease released by mast cell degranulation,
provides additional diagnostic clue and should be performed whenever feasible.
Total serum tryptase levels above 25 μg/L suggest an IgE-related mechanism.3
Increased total tryptase level is not specific to anaphylaxis and can be raised in
other unrelated conditions like myocardial infarction, amniotic fluid embolism,
or trauma. Conversely, tryptase levels may be normal if anaphylaxis is basophil
mediated.10,37,38 The half-life of tryptase is approximately 2 hours, and returns
to baseline levels within 12–14 hours.39 It is important to take at least two blood
samples for total tryptase—the first within 60 minutes of the reaction and the
second at 24 hours. Increased tryptase levels beyond 24 hours may indicate late-
onset anaphylaxis, biphasic reaction, or underlying mastocytosis or clonal mast
cell disorders.
Plasma Histamine
Elevated plasma histamine level correlates with signs and symptoms of
anaphylaxis and are more likely to be raised than are total serum tryptase levels.40
Plasma histamine levels reach the peak levels within 5–15 minutes of the onset of
anaphylaxis symptoms, and then gradually fall to baseline by 60 minutes because
of rapid metabolism. Blood samples for histamine require special handling:
blood should be drawn through a wide bore needle and kept cold at all times,
to be centrifuged immediately, and freeze the plasma promptly.41 However, this
is not specific for anaphylaxis and due to histamine’s short plasma half-life of
15–20 minutes, it is also difficult in practice to capture an elevated level during
resuscitation.
Urine Histamine
Histamine and its metabolites can be detected in the urine after anaphylaxis
and the increased levels are more specific than increase in plasma histamine for
anaphylaxis.
TREATMENT
Management of anaphylaxis should start immediately and the suspected drug
should be stopped.
Airway
Airway should be secured immediately and high flow oxygen should be given if
there are signs of respiratory distress. Intubation could be difficult in patients in
whom the upper airway anatomy is edematous and distorted. Repeated failed
attempts can lead to complete airway obstruction and may be fatal. This may
require an emergency cricothyroidotomy.
Epinephrine
Prompt administration of epinephrine with close hemodynamic monitoring is the
mainstay of treatment. The main factor associated with mortality by anaphylaxis
is the delay in epinephrine administration.42 A publication of a series of fatal
anaphylactic reactions revealed that epinephrine was used in 14% of patients
only, prior to cardiac arrest.43
The a-1 adrenergic agonist effects of epinephrine increase peripheral
vascular resistance and decrease airway mucosal edema. It is b-1 adrenergic
agonist effects result in increased inotropic and chronotropic effects on heart. The
b-2 adrenergic agonist effects result in bronchodilation and also has inhibitory
effects on the release of inflammatory mediators from basophils and mast cells.44
Epinephrine in an initial dose of 10–20 µg IV for grade II anaphylactic
reaction and 100–200 µg IV for grade III reactions can be used. Additional doses,
if required, should not be delayed.3 If the patient requires repeated boluses, a
continuous infusion (0.05–0.4 µg kg-1 min-1) should be started. If intravenous
access is not available, epinephrine can be injected intramuscularly at the lateral
thigh till IV access is established. Excessive administration on the other hand, can
cause ventricular arrhythmias, pulmonary edema, and hypertensive crisis.
Intravenous Fluid Resuscitation

It involves repeated boluses of 20 mL kg-1 intravenous isotonic crystalloids,
to fill the dilated peripheral vessels and to compensate for plasma leakage to
extravascular space.45,46 The total amount of crystalloids required may vary from
2 L to up to 10 L IV.46,47
Other Drugs
If there is persistent hypotension, other vasopressors like norepinephrine or
vasopressin may be used. Response to epinephrine may be suppressed in
patients on beta-blockers, angiotensin-converting enzyme inhibitors, or those
who have a spinal blockade. In patients taking beta-blockers, glucagon can be
given to treat hypotension because its inotropic and chronotropic effects are not
mediated through beta receptors.48 Glucagon may be given in a dose of 1–5 mg
in adults and 20–30 µg kg-1 to a maximum of 1 mg in children intravenously over
5 minutes. If required, this dose may be followed by an infusion of 5–15 µg min-1.
Beta-adrenergic agonists such as salbutamol or nebulized epinephrine can
be used to treat bronchospasm. Sugammadex, a reversal agent for rocuronium
and vecuronium, may reverse anaphylaxis triggered by rocuronium.49 After the
initial resuscitation of the patient, steroids and antihistamines can be considered.
However, both drugs have slow onset of action and have not been shown
to improve the clinical outcome.11 Corticosteroids can also be used to treat
bronchospasm, and their administration also helps to prevent the late phase of
anaphylactic shock.46,47 Hydrocortisone 200 mg IV bolus (or 5 mg kg-1) is followed
by 100 mg (2.5 mg kg-1) IV every 6 hours or methylprednisolone 125 mg IV is given
every 6 hours.46,47 Finally, in case of cardiac arrest, advanced cardiac life support
(ACLS) measures should be applied.3
When intraoperative anaphylaxis occurs, the surgery should be completed
as early as possible and the patient should be shifted to the intensive care
postoperatively for monitoring because the condition can be prolonged up to
32 hours and biphasic reactions occur in up to 20% of cases. Several hypotheses
of biphasic reaction include inadequate treatment of the initial reaction, release
of late-phase mediators from immune cells, delayed absorption of the antigen
into the systemic circulation, and activation of secondary mediator pathways.50
Mild nonanaphylactic reactions, with skin manifestations can be treated
with H1 antihistamines (diphenhydramine 25–50 mg or 0.5–1 mg kg-1 IV or
dexchlorpheniramine 5 mg IV) with H2 antihistamines (ranitidine 50 mg IV).3,45
PREVENTION OF ANAPHYLAXIS
Patients who suffer from perioperative anaphylaxis should be properly
investigated to avoid re-exposure to the causative agent and prevent potentially
fatal outcomes. In case of perioperative anaphylactic reactions, the intraoperative
charts of vital signs with names of drugs and their time of administration should be
recorded and reported by the anesthesiologist, allowing adequate interpretation.
Investigation of a drug adverse reaction is challenging. Specific investigation for
the suspected drug or agent should ideally be conducted 4–6 weeks after the
reaction, because there can be a depletion of both mast cell/basophil mediators
and in specific IgE antibodies after anaphylaxis.3,45,51,52
Skin tests (Skin Prick test and Intradermal Test) are generally done 4–6 weeks
after a reaction for common allergens, including neuromuscular blocking agents,
intravenous and local anesthetics, antibiotics, latex, chlorhexidine, colloids, and
blue dyes. Skin tests to NMBAs may remain positive for years, whereas positivity
to beta-lactams will decline with time. They are less helpful in diagnosing allergy
to opioids, NSAIDs, and paracetamol, in which cases, oral challenge tests may be
needed instead.53
At the end of the allergic work-up, the patient should be informed about the
agent which was found positive, and a warning card should be issued on the
results of tests and advice for future surgeries.35
FUTURE ANESTHESIA MANAGEMENT

The safest approach for a patient with the history of perioperative anaphylaxis is
the recognition of the trigger agent and to completely avoid its use. If the diagnosis
of a specific causative agent is not possible, then the management depends upon
avoidance of high-risk agents and to implement general precautions.
General precautionary measures before a repeat anesthesia include optimal
preoperative control of asthma, slow administration of antibiotics and other
high-risk agents, and if possible, to avoid beta blockers, Angiotensin converting
enzyme (ACE) inhibitors, and drugs that cause direct histamine release from
mast cells/basophils. Because the cross-reactivity is frequently observed with
NMBAs, all available muscle relaxants should be tested.37,54 Regional anesthesia
may be preferred although perioperative anaphylaxis has been reported in these
patients also.55
KEY POINTS
• A naphylaxis is a severe, potentially life-threatening systemic hypersensitivity reaction.
• It can be caused by immunological mechanisms, nonimmunological mechanisms or
be idiopathic.
• Anaphylaxis is a clinical diagnosis, and the management remains same irrespective of
the cause.
• Common agents that may cause perioperative anaphylaxis are antibiotics,
neuromuscular blocking agents and latex.
• It is difficult to diagnose intraoperatively, as patients are covered by drapes, are sedated
or unconscious and are unable to report pruritis.
• The anesthesiologist plays a key role in coordinating care for the patient during and
after perioperative anaphylaxis.
• Early recognition and administration of adrenaline is the mainstay of anaphylaxis
management.
• Steroids and antihistamines have no role in the early management of anaphylaxis.
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36. Mertes PM, Lambert M, Guéant-Rodriguez RM, Aimone-Gastin I, Mouton-Faivre C,
Moneret-Vautrin DA, et al. Perioperative anaphylaxis. Immunol Allergy Clin North Am.
2009;29(3):429–51.
37. Laroche D, Vergnaud MC, Sillard B, Soufarapis H, Bricard H. Biochemical markers
of anaphylactoid reactions to drugs. Comparison of plasma histamine and tryptase.
38. Sala-Cunill A, Cardona V, Labrador-Horrillo M, Luengo O, Esteso O, Garriga T, et al.
Usefulness and limitations of sequential serum tryptase for the diagnosis of anaphylaxis
in 102 patients. Int Arch Allergy Immunol. 2013;160(2):192-9.
39. Schwartz LB, Yunginger JW, Miller J, Bokhari R, Dull D. Time course of appearance and
disappearance of human mast cell tryptase in the circulation after anaphylaxis. J Clin
Invest. 1989;83(5):1551-5.
40. Vadas P, Perelman B, Liss G. Platelet-activating factor, histamine, and tryptase levels in
human anaphylaxis. J Allergy Clin Immunol. 2013;131(1):144-9.
41. Simons FER, Frew AJ, Ansotegui IJ, Bochner BS, Golden DBK, Finkelman FD, et al. Risk
assessment in anaphylaxis: current and future approaches. J Allergy Clin Immunol.
2007;120(1 Suppl):S2-24.
42. Liew WK, Williamson E, Tang MLK. Anaphylaxis fatalities and admissions in Australia.
J Allergy Clin Immunol. 2009;123(2):434-42.
43. Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal reactions.
Clin Exp Allergy J Br Soc Allergy Clin Immunol. 2000;30(8):1144-50.
44. Vadas P, Perelman B. Effect of epinephrine on platelet-activating factor-stimulated
human vascular smooth muscle cells. J Allergy Clin Immunol. 2012;129(5):1329-33.
45. Hepner DL, Castells MC. Anaphylaxis during the perioperative period. Anesth Analg.
2003;97(5):1381-95.
46. Longrois D, Lejus C, Constant I, Bruyère M, Mertes P-M. Treatment of hypersensitivity
reactions and anaphylactic shock occurring during anaesthesia. Ann Fr Anesthèsie
Rèanimation. 2011;30(3):312-22.
47. Galvão VR, Giavina-Bianchi P, Castells M. Perioperative anaphylaxis. Curr Allergy
Asthma Rep. 2014;14(8):452.
48. Thomas M, Crawford I. Best evidence topic report. Glucagon infusion in refractory
anaphylactic shock in patients on beta-blockers. Emerg Med J. 2005;22(4):272-3.
49. Simons FER, Ardusso LRF, Dimov V, Ebisawa M, El-Gamal YM, Lockey RF, et al. World
Allergy Organization Anaphylaxis Guidelines: 2013 update of the evidence base. Int
Arch Allergy Immunol. 2013;162(3):193-204.
50. Tole JW, Lieberman P. Biphasic anaphylaxis: review of incidence, clinical predictors,
and observation recommendations. Immunol Allergy Clin North Am. 2007;27(2):309-
26, viii.
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for skin test procedures in the diagnosis of drug hypersensitivity. Allergy.
2002;57(1):45-51.
52. Soetens F, Rose M, Fisher M. Timing of skin testing after a suspected anaphylactic
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53. Ewan PW, Dugué P, Mirakian R, Dixon TA, Harper JN, Nasser SM, et al. BSACI
guidelines for the investigation of suspected anaphylaxis during general anaesthesia.
Clin Exp Allergy J Br Soc Allergy Clin Immunol. 2010;40(1):15-31.
54. Schatz M, Fung DL. Anaphylactic and anaphylactoid reactions due to anesthetic
agents. Clin Rev Allergy. 1986;4(2):215-27.
55. Fisher M. Anaphylaxis to anaesthetic drugs. Novartis Found Symp. 2004;257:193-202-
210, 276-85.
CHAPTER 11
Effect of Anesthesia on
Perioperative Immunity
Anju Grewal, Nidhi Bhatia
INTRODUCTION
Immunity is the capability of our body to identify all foreign organisms as not
belonging to one’s own self and also to remember as well as resist them. These
‘non-self’ antigens can range from bacteria, viruses, fungi to cancer cells and
transplanted organs.1 Thus, immune response is the body’s protective defense
mechanism. On the other hand immune response can also be detrimental to our
body if it is exaggerated in the form of a hypersensitivity reaction.2 Hence, immune
response acts as a double-edged sword; depending upon the type of antigen and
antibody as well as personal susceptibility, it either protects or harms the body.2
COMPONENTS OF IMMUNE RESPONSE

The protective mechanism of immune response mainly involves two components:
Innate or nonspecific response and acquired or specific response.
Innate or Nonspecific Immunity

This is one of the most primitive sub-division of the immune system. This is the
primary defense that opposes the non-self invaders.1 Nonspecific immunity
does not need previous exposure to antigens and is determined genetically;
thus a wide range of targets can be neutralized in a nonspecific fashion.1,3 It
consists of humoral and cellular components, with the most important cells
being neutrophils, macrophages and lymphocytes.3 These cells are involved in
initiating the process of inflammation following tissue damage or infection.4
Anatomical barriers like the mucosal membranes and intact skin are vital parts of
the nonspecific immune system, which are breached by invasive procedures like
operative incisions and insertion of central lines.5
Acquired or Specific Immunity

This is an adaptive response that requires previous exposure to an antigen for
optimal function.3 This is the immune system that seeks out specific targets, with
the cells that confer specific immunity being capable of interacting with a limited
number of closely related antigens.1 Thus the response of acquired immune
system is characterized by:
• Delay: It takes a day-long process for the lymphocytes to be activated before
they start responding.
• Specificity: The antibodies are targeted to the proteins which are specific for
the intruding antigens.
• Memory: There is formation of dormant cells that protect the host from
re-exposures.
To summarize, the main aim of both specific and nonspecific immunity is to
prevent and detect infection, and clear damaged cells.5,6
PERIANESTHESIA STRESSORS
Perianesthesia period involves a number of events that can be stressful and
adversely affect the immune functions. These include:4,7-9
• Stress response to surgical intervention: The fear, anxiety and pain of surgical
intervention can induce neurohumoral stress response, resulting in
sympathetic nervous system and hypothalamus activation with increase in
plasma cortisol and catecholamine levels. Cortisol combines with cytosolic
receptors of immune cells; with the resulting biochemical signaling cascade
depressing the cellular function and adaptive as well as innate immune cells,
thus significantly decreasing overall immunity. Increased catecholamine
levels also reduce immune responses via interaction with a and b cell surface
receptors and also by mediating a shift towards T-helper cell subtypes, which
do not result in effective cellular immunity.
• Hyperglycemia: Perioperative stress response resulting in elevated levels
of catecholamines and cortisol causes a catabolic state with increased
metabolism of proteins, fats and starches into glucose molecules. Chronic
activation of the microvasculature endothelial cells by glucose molecules
impedes the immune cell migration to areas of inflammation or infection.
• Hypothermia: Decreased core body temperature due to large invasive
surgeries and fluid shifts can hamper effective tissue oxygenation. Even mild
hypothermia in the perioperative period, may cause thermoregulatory vessel
constriction, resulting in decreased tissue oxygenation. The resultant tissue
hypoxia can interfere with wound healing as a result of impaired oxidative
killing by neutrophils and reduced collagen deposition.
• Inflammatory response to surgery: Damage to the body tissues by surgical
procedures can provoke inflammatory response by innate immune cells, which
is directly related to the magnitude of surgical invasiveness. Proinflammatory
cytokines in turn lead to depressed lymphocyte function. This depressed
adaptive immunity is directly related to the degree of activation of innate
immunity.
ANESTHESIA AND IMMUNITY

The possibility that anesthesia may have an effect on the immuno logical
functions was considered in 1903, when it was reported that anesthetic agents
like chloroform, ether and chloral hydrate could increase the death rate from
anthrax in guinea pigs.10 Both anesthesia as well as surgery dramatically
increase the inflammatory response accompanied by a decrease in the function
of cell-mediated immune response system. Depression of immune response
may decrease host defense ability, subsequently increasing the possibility of
postoperative infection and neoplasm proliferation in cancer patients.11
Effect of Anesthesia on Perioperative Immunity 133
Separation of the individual effects of various perioperative events, including

surgical procedures and anesthetic interventions, on the immune response
of the patients is rather difficult. Moreover, it is also not easy to determine the
overall effect of these interventions on the immune system function.2 In general,
the factors affecting the magnitude of immunity changes include surgical
duration, intraoperative blood loss and invasiveness of the procedure, degree
of preoperative anxiety and severity of postoperative pain experienced by the
patient.12 In recent years, the response of the immune system to anesthesia has
generated a lot of interest, though the effects anesthesia has on immunity has
not been extensively evaluated. Reports which have investigated the immune
response to anesthesia, do not agree with the fact that “what immunologic
changes occur in a particular narrow space of anesthesia and which side-effects
may occur due to these changes”.13 However, a number of extensive reviews
have revealed that anesthesia can adversely affect both innate and acquired
immunity.3 Though the specific mechanisms by which anesthetic drugs affect
the immune system still remain unclear, but anesthetic drugs induce analgesia
affecting the transmission of nerve impulses, and they modulate surgical stress
by acting on the hypothalamus–pituitary–adrenal axis, affecting catecholamines
and glucocorticoid secretion. Thus, part of the effect anesthesia has on immunity
would be due to its action on the well-known immunomodulatory effect of
glucocorticoids.14
ANESTHETIC AGENTS AND IMMUNITY

Numerous previous reports have studied the effect of intravenous as well as
inhaled anesthetics on the function of immune cells.15-19 Though it has been
reported that anesthetics may have multiple and conflicting effects on immunity,
however in most circumstances, volatile and intravenous anesthetic agents are
known to depress immune cell functions. Further, following general anesthesia,
slight fall in the levels of immunoglobulins (IgM, IgG and IgA antibodies) in the
postinduction as well as the postoperative period has been reported. This may be
a result of formation of immune complexes and also due to hemodilution.2
Inhalational Agents and Immune Functions

• Isoflurane, in high concentrations, inhibits the generation of superoxide by
neutrophils; whereas its low concentration increases superoxide formation.
Further, superoxide formation by neutrophils is also inhibited by nitrous
oxide, halothane and enflurane. Paradoxically, though superoxide generation
by neutrophils is inhibited by anesthesia exposure, however, anesthetics
increase endothelial cell target sensitivity to oxidants. Thus, inhalational
agents like halothane and isoflurane increase the endothelial cell cytotoxicity
of activated neutrophils.20,21
• Anesthetic drugs affect both monocyte circulating levels and functionality.
Sevoflurane decreases circulating monocytes without af fecting their
phagocytic activity. Experiments carried out with halothane have contributed
to understand the tissue specialization of macrophages. Halothane does
not have an effect on spleen macrophage phagocytic activity, but enhance
peritoneal macrophage phagocytosis and respiratory burst.22,23
• Inhalational agents like isoflurane and halothane are known to inhibit the
natural killer cell (NK cell) cytotoxicity.24 Brand et al.25 found that thiopental,
fentanyl and isoflurane significantly decreased the levels of circulating NK
cells and increased the number of B cells and CD8+ T-lymphocytes. Further,
Durlu et al.26 concluded that both isoflurane and sevoflurane were almost
comparable with regards to the immunological superiority.
• Inhalational agents are known to increase blood cortisol levels, with isoflurane
resulting in significantly greater increase, as compared to halothane and
sevoflurane.
• Cytokines such as interleukin-1 (IL-1), 6, 8, 10 and TNF-g are produced and
released mainly by the innate immune cells. Anesthetic agents can affect the
production of these cytokines.14 Inhalational anesthetic agents are known to be
associated with increase in interleukin-2 (IL-2) and IL-6. Schneemilch et al.27
have also reported that there is a significant increase in plasma concentration
of IL-6 both during and after surgery with balanced inhalation anesthesia.
This increase is not known to have any relation to pain.
Intravenous Agents and Immune Functions

• NK cell cytotoxicity is inhibited by intravenous agents. Propofol is known to
induce an increase in NK cell count and also decrease cytotoxic activity.27
• Oxygen consumption is known to increase after phagocytosis. This results
in increase in the activity of hexose monophosphate shunt with formation of
hydrogen peroxide and oxygen.2 This is known as the respiratory burst. Intra
venous anesthetics like propofol, thiopentone and midazolam are known to
inhibit both phagocytosis and respiratory burst. However, Davidson et al.28
reported that ketamine and thiopentone reduced the neutrophil respiratory
burst when they were used at concentrations greater than that used in routine
clinical practice.
• Ketamine, thiopentone, propofol and opioids are known to decrease IL-1
levels and increase IL-10 levels. They also inhibit the liberation of TNF-a from
the mononuclear cells. IL-6, produced mainly by monocytes, macrophages
and T-lymphocytes is known to affect adaptive immune response, stimulate
antibody production and enhance IL-2. Propofol increase I L-6 levels, whereas
thiopentone, ketamine and opioids decrease its concentration.29-31
• Clinically used doses of ketamine can depress the endotoxin-induced
macrophage activation through activation of protein kinases, nuclear factor-
kappa B and activator protein-1. Ketamine has been shown, in both human and
animal models, to possess anti-inflammatory effects, and several studies have
provided in vitro data demonstrating that this intravenous anesthetic could
inhibit the function of lymphocytes, NK cells, and neutrophils. The NK-cell
cytotoxic activity is significantly reduced by ketamine, and an injected lung
tumor has shown increased metastasis after ketamine treatment. Ketamine
also suppresses macrophage activity via inhibition of phagocytic and oxidative
functions, and TNF-a, IL-1b, and IL-6 mRNA syntheses.32
Opioids and Immune Functions33,34

Opioids are one of the most commonly used drugs in the perioperative period as
well as for chronic pain management. Previous reports in literature reveal multiple
and conflicting effects of opioids on immune functions. In general, opioids are

known to have an immunosuppressive effect. Morphine, in animal studies,
has shown to inhibit lymphocyte and cytokine production as well as NK-cell
activity. Though fentanyl is also known to depress immune function, however,
its immunosuppressive effect is mainly seen in the initial 72 postoperative hours.
Researchers have also shown that animals who have received postoperative
analgesia with fentanyl or intrathecal morphine are known to have a significantly
lower tumor burden than animals without pain relief. In contrast to these effects
of morphine and fentanyl, tramadol does not depress immunity. It has also been
stated that after giving opioids, the pain relief that is produced may result in
decreased stress and sympathetic outflow. The result is a reduction in circulating
cortisol and catecholamine levels. Thus, though the direct effect of opioids,
in the absence of pain, may depress immune functions, however, when used
for analgesia, opioids limit pain and sympathetic outflow. Thus the pain relief
produced by opioids results in balancing the autonomic system and restoring
immunity.
ANESTHETIC TECHNIQUES AND MALIGNANCY

Development of postoperative infections as well as postoperative metastasis are
known to be analogous. In both circumstances, it is believed that decrease in
the host defense mechanisms in the perioperative period can have deleterious
consequences as this is a critical period.35
Response of Intact Immunity to Tumor

Intact cellular immunity is considered vital for the prevention of development
of metastasis.35 Evasion of cellular immune system of the host is the key step to
metastatic development. Main protection against cancer cells is provided by NK
cells. Animal studies have shown that reduction in NK cell activity by stress can
enhance tumor development. Cytotoxic T cells, dendritic and mononuclear cells
also result in decreased metastatic functions.35
Effect of Surgery on Metastatic Development35

Human studies have revealed that surgery itself can increase metastatic
development. The proposed mechanisms are:
• Tumor cell release into circulation by tumor handling and disruption during
surgery.
• Angiogenesis maybe inhibited by the presence of primary tumor. Safeguard
against angiogenesis maybe eliminated by removal of the tumor. This may
result in growth and survival of minimal residual disease.
• Growth factors that are released both locally and systemically during surgery
may promote tumor recurrence.
• The perioperative immunosuppression due to surgery, anesthesia and other
related perioperative factors may result in depression of cellular immunity for
days.
Effect of Anesthetic Agents on Malignancy and

Metastatic Development35
• Intravenous agents like propofol, thiopentone and ketamine are known to
reduce the number and activity of NK cells in animal models.
• Volatile agents decrease the NK cell cytotoxicity in animal models. However,
exposure of patients to increased number of drugs and presence of confounding
variables makes interpretation of human data difficult. However, general
anesthesia is known to decrease circulating NK cells in elective orthopedic
surgical patients. It also impairs neutrophil, dendritic, macrophage and T-cell
function in humans.
• Nitrous oxide is known to increase metastasis in lungs and liver in animal
models. However, nitrous oxide has not been found to have any effect on
cancer recurrence in humans undergoing surgery for colorectal carcinoma.
• Local anesthetics also show cytotoxic effects on tumor cells. At clinically
used concentrations, lidocaine is known to inhibit epithelial growth factor
receptor, thereby inhibiting proliferation of tumor cells. It also decreases the
invasiveness of human cancer cells. Ropivacaine is also known to suppress the
in vitro cancer cell growth in patients suffering from ulcerative colitis.
• Both cellular and humoral immunity is decreased by periope ra
tive and
chronic opioid administration. This includes phagocytic activity, NK-cell
activity, antibody and cytokine production.
Effect of Regional Anesthesia on Malignancy36-39

In animal models regional anesthesia is known to decrease the development of
metastasis. Though there is lack of published prospective human trials evaluating
the effect regional anesthetic techniques have on cancer recurrence, however
retrospective studies have shown their beneficial effect on cancer metastasis.
There are three possible mechanisms that can explain this benefit:
1. The immunosuppressive effects of surgery can be diminished by regional
anesthesia, as there is a decrease in neuroendocrine stress response by giving
regional anesthesia.
2. Perioperative opioid requirements are decreased by administering regional
analgesia. Cell mediated immune responses may themselves be inhibited by
opioids.
3. When regional anesthesia is used along with general anesthesia, the amount
of general anesthetics required during surgery is decreased.
Effect of Blood Transfusion

The risk of tumor recurrence and metastasis is increased with perioperative
allogenic blood transfusion. This may be due to the fact that allogenic blood
is known to have immunosuppressive effects, also called transfusion related
immunomodulation (TRIM).35 One of the mechanisms cited for TRIM, in animal
studies, is the allogenic white blood cell transfusion. Further, following transfusion
of blood products, there may be a decrease in the levels of tumor necrosis factor
(TNF), T-cytotoxic lymphocyte production and macrophage chemotaxis into the
site of infection.40 The risk of metastases is greater in patients with malignancies
due to transfusion-induced immune suppression. Blood transfusion can also

inhibit antigen recognition.
ANESTHESIA AND ANAPHYLAXIS

Immune response is considered to be a protective phenomenon against any
foreign antigen. However, when this response is exaggerated, also known as
hypersensitivity, it may prove to be detrimental to the body. Hypersensitivity
can be a result of foreign agents, chemicals, drugs and environmental antigens.
The most common type of hypersensitivity in anesthesia practice is anaphylaxis.
This is one of the most life threatening allergic reaction that is mediated by IgE
antibodies. The manifestation and course of anaphylaxis may be different in
various individuals, ranging from minor clinical features like coughing, sneezing,
itching to full-blown syndrome with hypotension, tachycardia, arrhythmias;
finally resulting in death.2 The occurrence of anaphylaxis is often severe,
unpredictable and without any previous history of allergy.
IMMUNE FUNCTION AND PERIANESTHESIA CARE: CLINICAL

IMPLICATIONS
As has been discussed, the surgical intervention, perianesthesia environment and
anesthesia drugs may affect immune function. Certain clinical recommendations
to guide anesthesia care which supports immune function include:
• Measures to decrease the surgical stress response should be taken, especially
in patients with pre-existing depressed immunity like extremes of age,
inadequate nutritional status, preoperative sepsis or infection, diabetes,
cancer, etc.
• Use regional anesthesia and analgesia wherever possible. Pain should be
effectively treated using systemic or neuraxial opioids. Though opioids may
directly depress immunity, their administration also helps in indirectly
preserving immune functions by inhibiting production of stress hormones.
• Avoid hyperglycemia in patients at an increased risk of immune suppression
undergoing major surgeries.
• Assess and prevent hypothermia.
• Ensure adequate tissue perfusion so as to maintain adequate delivery of
nutrients as well as oxygen to circulating immune cells.
• Keep arterial pO2 values within normal limits.
• When appropriate, consider minimally invasive surgical approaches.
• Administer antibiotics prior to surgical incision or as previously scheduled.
• In immunocompromised population, try to avoid blood transfusion unless its
administration is clearly indicated clinically.
CONCLUSION
It is now well established that the perioperative period is frequently associated
with transient depression of adaptive immunity. Immunosuppression may be a
significant cause of increased morbidity and mortality in high risk populations.
Recent evidence supports the fact that both innate and acquired immunity can
be influenced by anesthetic agents. However, the precise role of anesthesia alone
as a causative factor for development of perioperative immunosuppression

remains to be established. By a better understanding of these defects, and by
meticulous perioperative management, we may however be able to decrease
patient morbidity and mortality.
KEY POINTS
• I mmune response is a protective mechanism which helps the body to identify all
foreign agents as not belonging to one’s own self. It involves two components: specific
or acquired and nonspecific or innate immune response.
• Perianesthesia events that are extremely stressful and can adversely affect the immune
functions include stress response to surgical intervention, hyperglycemia, hypothermia
and inflammatory response to surgery.
• Anesthesia can adversely affect both innate and acquired immunity.
• Inhalational agents increase endothelial cell cytotoxicity of activated neutrophils,
affect both monocyte circulating levels and functionality, inhibit natural killer cell (NK
cell) cytotoxicity, increase blood cortisol levels and increase interleukin-2 (IL-2) and IL-6
levels.
• Intravenous agents inhibit NK cell cytotoxicity, inhibit both phagocytosis and
respiratory burst, decrease IL-1 levels and increase IL-10 levels.
• Clinically used doses of ketamine can down-regulate endotoxin-induced macrophage
activation and can counteract inflammation.
• Though the direct effect of opioids, in the absence of pain, maybe depression of
the immune functions, however, when used for analgesia, opioids limit pain and
sympathetic nervous system activation.
• Decrease in the host defense mechanisms in the perioperative period can have
deleterious consequences as this is a critical period.
• Patients with malignancies have greater risk of metastases as a result of transfusion-
induced decrease in immunity.
• Exaggeration of immune response is called hypersensitivity. The most common type of
hypersensitivity in anesthesia practice is anaphylaxis.
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39. Moller JF, Nikolajsen L, Rodt SA, et al. Thoracic paravertebral block for breast cancer
surgery: a randomized double-blind study. Anesth Analg. 2007;105:1848-51.
40. Waymack JP, Fernandes G, Cappelli PJ, et al. Alteration in host defense associated with
anaesthesia and blood transfusions. II: Effect of response to endotoxin. Arch Surg.
1991;12:59-62.
CHAPTER 12
Nontechnical Skills for
the Healthcare Provider:
Bringing about Changes in Outlook, Protocols and Policies
Hema C Nair
INTRODUCTION
Nontechnical skills are cognitive and social skills of a professional or a team that
complement technical skills to achieve safe and effective performance. They are a
concept that is currently on the forefront of Human Factors Engineering, a closely
associated field within psychology, which seeks to address the need for optimal
functioning in the increasingly complex work environment that we inhabit today.
It deals with the challenges faced when professionals have to work closely with
each other and also with machines and equipment in order to achieve optimum
results while reducing mishaps and errors. They are not a substitute for technical
skills, but an adjuvant to ensure that these technical skills are employed effectively
for best results.
Healthcare services are a very complex workspace where teams have to
perform optimally together and with technology in order to deliver safe care to
the patient. Particularly in the operating rooms, these results are expected in a
stressful environment while dealing with critical events. In case of a single weak
link in this chain of events, outcome can change, and the patient can be put in
jeopardy. In this scenario, behavioral attributes like communication, anticipation,
awareness and discipline can significantly affect how a given situation is dealt with
and giving in to autocratic behavior or panic can have disastrous consequences.
Training in nontechnical skills helps in understanding this aspect of professional
behavior and modifying it can improve outcomes.
Of all the healthcare environments, nowhere are nontechnical skills more
important than in the operating rooms. Here, technical competence, interpersonal
skills, resource utilization, technology and equipment has to work seamlessly
in a time-pressured environment; and conflict within these relationships can
contribute to increased potential for adverse events and impact negatively on
patient care.1
Research has shown that 43% of all adverse events in healthcare services
occur to surgical patients; reflecting the intensive nature of intervention these
patients go through.2 A careful study of the causative factors has shown that
these are contributed to by failings in both technical expertise and non-technical
performance of the caregivers.3 Effective communication between team members
and co-operation are significant contributors towards smooth work flow and
better outcomes and breakdown in these are often associated with mishaps and
strife in the work environment ultimately resulting in a stressful situation where
critical events can occur.4,5
The importance of nontechnical skills was first studied and implemented in

the airline industry as NOTECHS in the 1990s. They found that mishaps often
occurred secondary to pilot error, lack of communication or poor decision making
and that training them to have better cognitive and social skills can significantly
reduce these errors. The results of this are self-evident, in that commercial air
traffic is currently one of the safest mode of transport barring incidents of wilful
violence or terrorist attacks.
At the beginning of this century, noting the significant incidence of human
errors contributing to morbidity in healthcare, this concept was introduced in an
attempt to reduce adverse events from human factors. Healthcare professionals
were trained in honing their nontechnical skills and the results were studied to
prove their efficacy. They have since been modified to suit each professional
stream and adapted to their specific requirements. Anesthesiologists are trained
in anesthesia nontechnical skills also, know as ANTS, and similar acronyms are
used in other fields such as SPLINTS for surgical scrub nurses and NOTSS for
surgeons6.
GENESIS OF NONTECHNICAL SKILLS IN HEALTH CARE

‘To err is human report’ published in 1999 by The Institute of Medicine, a
distinguished medical body that provides public policy advice to the US congress,
established that 98,000 people die annually from errors in healthcare.7 This was
widely reported in the media and the most effective analogy used to highlight the
extent of this disaster was to compare it to the crash of a wide bodied jet leaving
no survivors, every other day. When expressed in this manner, the other fact that
draws our attention is the enviable safety record that we witness in the aviation
industry today. Health care and commercial air travel has several interesting
parallels; both are intensely technology driven and have deep impacts on human
lives. Breakdown in communication and poor leadership skills are known to have
caused friction in an airplane cockpit and almost 70% of aviation accidents were
attributed to pilot errors. When studied in depth, it appeared that these were
caused in equal parts by unsafe designs in console panels, lack of team work and
communication in the cockpit and poor decision making.
An example of airplane mishap which had its roots in an enforced human
error, was the accidents that happened to several kinds of military airplanes in
the US air force, where the pilots retracted the landing gear wheels when they
meant to retract the wing flaps, soon after landing. It was observed that this error
occurred with remarkable frequency even with skilled pilots. This was clearly not
a deficiency of technical skill or expertise, and careful study of the panel design
showed that the identical controls mounted so close together was what caused
these mishaps. These errors were completely eliminated by modifying the tips
of these controls to have a different shape and texture, so that the pilots did not
mix them up, even if they did not look while deploying them. This important
intervention that happened in 1943 was the precursor to the touch coding system
that we use in anesthesia machines today, and is based on the application of
non-technical skills in healthcare industry. NOTECHS also highlighted to us the
importance of good team work and communication in making the workspace
safe for our patients and pleasant for us.
Nontechnical Skills for the Healthcare Provider... 143
In medicine like in an airline cockpit, there is a rigid hierarchical system

and most juniors are unwilling to challenge the decisions made by more senior
staff. This reluctance can be damaging as illustrated in the following example.
Most people who gravitate towards positions of authority develop a strong
personality which does not take criticism or suggestions very easily. This is aptly
demonstrated in the case of a United Airlines flight that crashed due to engine
failure from an empty fuel tank. The diffident junior crew members noticed
the diminishing fuel levels while the plane was circling for more than an hour
while trying to deal with a faulty landing gear, but they were too fearful of the
authoritative captain to bring it to his notice. The plane crashed killing 10 and
injuring 23 others.8 This breakdown in teamwork and communication is due to
an evident lack of nontechnical skills.
In the career of most doctors, we would have encountered a similar situation
either as a junior who was hesitant to talk to a consultant, or a consultant who
would’ve taken offence at the comments from a junior. Similar breakdown in
communications can also happen if the reverse occurs, and the seniors are not
consulted on a matter of management and patient care can suffer.
This is amply demonstrated in this case scenario which unfolded in an
orthopedic operating room while a patient was waking up after scoliosis
surgery. These observations on nontechnical skills took place as part of a quality
improvement project in surgical teams. During surgery, the intraoperative
monitoring of motor-evoked potentials showed some changes prompting the
operating surgeon to want to assess limb power after the surgery. This was not
possible because the patient took an inordinately long time to wake up. She
was very drowsy and not obeying commands to move limbs, and the cause
was believed to be clonidine administered for pre-medication. Some strife and
distrust was witnessed between the surgical and anesthetic teams with one
resorting to blame game and the other getting defensive, while the situation with
the patient remained the same and no tangible solution was sought. Also there
was a communication breakdown between the junior anesthetist and consultant,
because the junior felt clonidine should not have been given, but discussed the
issue with the surgeon rather than advising his own consultant about it. Further
attempts at salvaging this situation were also poorly handled with the consultant
giving naloxone, which was an inappropriate drug to be given in the situation.
Neither the surgeon, nor the junior anesthetist objected to it at the time although
they had a discussion about it, critiquing the anesthesia consultant while the
latter was out of earshot. All these show a complete breakdown of teamwork,
decision making and problem solving and resulted in strife in the operating room
during a difficult post surgical scenario. This impacted negatively on patient care
and the neurological assessment had to be deferred until later.
CLASSIFICATION AND NONTECHNICAL

SKILL ASSESSMENT TOOLS
Nontechnical skills are inherent in most professionals in differing degrees, and
the key is to capture these and use them in order to train those who are lacking
in it. For ease of understanding and application of the skills so that they can be
dispersed among the anesthetists, they are classified into 4 major categories.
Performance is also graded in four degrees to help in quantification.
Fig. 12.1 Tools used in classification and categorization of nontechnical skills
Categories of Nontechnical Skills

• Leadership and management
• Teamwork and cooperation
• Problem solving and decision making
• Situational awareness.
In order to help the assessor with categorizing into these groups, several
prompters are also provided, as illustrated in Figure 12.1.
As the diagram suggests, there is always an area of overlap where behavior
patterns will fall into one or the other category, and it is incumbent on the assessor
to slot them into a specific category.
Once a certain category of nontechnical skill has been identified and assessed,
we attempt to quantify it (Table 12.1). Understandably soft skills such as these
are intangible and difficult to measure and the tools are used to simplify and
standardize the process. These tools are standard ones used to classify human
behavior by psychologists and human factors scientists.
Grading of Nontechnical Skills

When an individual or team is assessed for nontechnical skills, the behavioral
instances are captured by a trained observer and a scoring done. The scoring can
be shared with the subject as well as the institute of affiliation. A good score acts as
a positive feedback, encouraging the doctor to maintain the skill and in instances
Table 12.1 Quantification scale used in nontechnical skills

1. Below standard Directly compromised patient safety and effective teamwork
2. Basic standard Behavior in other conditions could directly compromise patient safety
and effective teamwork
3. Standard Maintains an effective level of patient safety and teamwork
4. Exceeds standard Enhances patient safety and teamwork. A model for all other teams
of deficiency, an impartial third party feedback can be given and further training
will help in improving these soft skills.
PRACTICAL APPLICATIONS OF NONTECHNICAL

SKILLS ASSESSMENT
Described below are a few instances of scoring of nontechnical skills as they were
assessed in a team. The tool used in this instance is a modification of NOTSS
which is nontechnical scoring for surgeons.
Case 1: ENT list—A case of Adenotonsillectomy

Category Role Team Score Remarks on incident capture
Leadership S2 Surgical 4 Does a complete time out mentioning name and side
and of surgery, introduces himself to the new anesthesia
Management resident since he was not present at the huddle.
The team members were coded to maintain objectivity and anonymity from
other team members. At the time of final data collation, the roles were decoded,
and the individuals debriefed about their performance. In this instance a brief
insight is given into the superior nontechnical skills of the main operating
surgeon who has performed all the safety checks prior to the start of the case,
and familiarized himself with a new team mate, so that later on in the day as the
case proceeds, communication will be easier. In contrast to the above instance,
unfolding of a poor score is illustrated below.
Case 2: Plastic Surgical Team—Surgical Resident under Observation

Situational S6 Surgical 2 Is overeager to do the timeout, even though the
awareness anesthesia team is busy inducing and not able to
participate, she is very new, not cognizant of S2’s
methods or choice of antibiotics and so is able to
contribute little to the time out apart from introducing
herself. When A1 checks with her about the procedure,
she says she will have to check with S2.
In the above example, the junior surgical resident has undertaken the task
of timeout, without being qualified for it. This demonstrates not just her lack of
understanding of the importance of a presurgical timeout, but lack of situational
awareness in that she was not helping towards the smooth conduct of the case,
but was actually interfering at the time of anesthesia induction.
Case 3: Endoscopy List—High Turnover Short Case Scenario where

Intravenous Anesthesia was Administered Using Infusion Pumps
Situational A1 Anesthe- 2 Is looking onto the surgical site and talking with
awareness siology the surgeons, and does not register the beeping of
the infusion pump immediately and takes time to
respond to it
Situational awareness for an anesthesiologist is just another word for

vigilance, which is actually one of the core competencies needed for the job. In
that regard, it can also be considered a technical skill. In this instance captured
here, the mistake was multifactorial in that distraction also played a role in poor
monitoring of the patient.
Case 4: Orthopedics List—Scoliosis Surgery where

Neuro-monitoring was Used
Category Role Team Score Remarks-on incident capture
Teamwork A1 Anesthe- 4 A1 mentioned that she would be using muscle
and siology relaxants (MR), E1 objected saying it would interfere
cooperation with their study of Motor-evoked Potentials (MEP). A1
explained, that they always used MR for intubations,
and that the effect would wear off long before they
checked the MEP, also that the SSEP would not be
affected. A potential conflict was resolved with
dialogue.
In this instance, the electrophysiological technician was only concerned about

recording of the MEPs and had very little understanding of anesthetic induction
or drugs used. The senior anesthesiologist in this case was accommodating and
took pains to explain the situation, thus reassuring the technician, who was also
only trying to do her job well.
The above examples have been chosen from a large quality control project
undertaken in the operating rooms, involving multidisciplinary teams. The
individuals and teams were studied and the results were tabulated and presented
to them as a feedback. Often when things go wrong during a surgery, the team
members are not able to objectively look at their performance and dissect the
mistakes made. By employing an impartial third party to make these observations,
facts are collected without bias and they can be informed about it later in a
non-judgmental manner.
MINOR ERROR CLASSIFICATION

Understanding of the impact of minor errors in health care is also essential for
reducing adverse events and resultant patient morbidity. Although minor errors
by themselves do not necessarily lead to catastrophes, multiple errors can lead to
a cascade effect and result in a major mishap. Acknowledging and willingness to
take responsibility for the errors is the first step towards mitigating these mistakes
and making sure that these happen rarely in future. As long as human input is
needed in a certain task, errors are inevitable, but training in nontechnical skills
can help dealing with it.
In a survey done by Flinn et al., 84% of anesthesiologists admitted to making
errors but believed that making errors is not a sign of incompetence.6 This fact
has been often repeated by psychologists when attempting to explain to people
that the reaction to human errors should not be ostracizing and punitive action,
but rather fool-proofing the system and having safety checks in place.9 Some
of the commonly made human errors in the anesthetic workspace is listed in
Table 12.2.
Table 12.2 Most commonly encountered human errors in anesthesia practice

Errors cited
Wrong drug administration
Operating list errors
Consent form problems
Disconnection of breathing circuits
Equipment problem/failure
Not checking anesthetic machine
Forgetting to complete tasks
Poor communication
Poor sterile technique/contamination
Limbs not marked/site errors
Operation by inexperienced staff
Premedication forgotten
Poor preparation/positioning
Shortage of equipment
The WHO check-list before starting a surgical case has helped immensely in
reducing many of these errors, and has been made mandatory in all hospitals
undergoing quality assurance certifications.10 Other methods adopted in this
regard are color coding of drug labels, anonymous incident reporting and written
down care pathway that accompanies a patient through the entire transfer from
hospital admission through ward and operating rooms and ICU to discharge.11
CHECKLISTS
Surgical intervention is very invasive and fraught with the possibility of morbidity,
and the chances of it happening increase exponentially in case of steps being
missed at any stage. In the UK, where numbers are far fewer than India; of the 230
million surgeries happening every year, 7 million face complications and almost
a million die.12 Although the disease process is the cause in a majority of cases,
rarely it occurs due to some oversight. This is a very tragic occurrence because
it is eminently preventable. This is where the importance of checklists come
in, because given the extensive nature of the procedures undertaken and the
magnitude of tasks to be carried out, it is inevitable that one or the other would
get missed. This is particularly true in stressful situations or when there is a sense
of urgency, which is most often the case. Checklists operate on the premise that
humans are fallible and that prompters for standard tasks are the easiest way of
preventing oversights. In 2007, the chair of the WHO declared the second global
safety challenge: ‘Safe surgery saves lives’. He constituted a committee to look into
implementing it in the UK and appointed Atul Gawande, a surgeon from Boston
with deep interest in patient safety and quality control to head the project. Dr
Gawande collected a team of surgeons, anesthesiologists, nurses, infection
control staff and human factors experts to undertake an evidence-based review
on the factors leading to patient harm in the perioperative period. It was from this
work, that the surgical safety checklist was derived.
Checklists were brought into clinical practice in 2008 by the WHO, and is now
followed in hospitals around the world. Although it is not mandatory, it has been
made a requirement by most certifying bodies like JCI and NABH (Fig. 12.2).
This checklist is not intended to be comprehensive. Additions and modifications to fit local practice are encouraged.
Fig. 12.2 Prototype of the WHO surgical safety checklist
HUMAN ERRORS RESULTING FROM TECHNOLOGY MISMATCH

The beginnings of the study and use of nontechnical skills started from a field
of psychology called Human Factors Engineering. This area of engineering dealt
with the ways to tailor the designing of technology in order to make it more user-
friendly for people. Contrary to the current belief, technology should not be more
complex to be useful. Although creators should create machines to perform more
and more complicated maneuvers in order to make life simpler for humans, the
use of this technology itself should be made very simple. If not, its use would
be subject to error and it would fail in its purpose. So in essence, it changes
technology to be user-friendly rather than expect people to adapt to it.13
This concept is of particular importance in healthcare, because we use
technology extensively in patient care and it has a high impact on them. Also
this technology is constantly evolving and taking on more and more functions
and responsibility. Although intended to make our jobs easier and improve care,
sometimes it can cause harm if used erroneously. When that happens, the normal
tendency is to blame the person who used this technology or programmed the
machine that resulted in the mistake. But when we look at it from a human factors
perspective, we see it differently. We realize that these mistakes are never made
willfully, and are often the result of a technology mismatch. Unless we deal with
that aspect of it, the chances are that it will recur, even if punitive action is taken
against the person who makes that mistake.14
The incident reported in literature which illustrates this point is the accidental
death of a young patient following morphine overdose and the indictment
of the nurse caring for her. In February, 2000 in a city in Florida, a 19-year-old
girl underwent a routine cesarean section and, on complaining of pain, was
administered intravenous morphine through a PCA pump. Seven hours later, she
died and the autopsy results showed 4 times the lethal dose of morphine in her
bloodstream. Evidently, there was an error in programming the PCA pump which
resulted in this massive overdose and death and all the blame was concentrated
on the nurse who programmed it. She was prosecuted for the crime by the state
attorney. What is not so evident at first sight and took the investigators some
time to uncover is that as far back as 3 years prior to the mishap, this model of
PCA pump was evaluated and found to be error prone. The ECRI (Emergency
care research institute) had issued an alert stating that this particular device
was susceptible to mis-programming and that the likelihood of that happening
is increased by the fact that the user interface and programming logic of the
pump are particularly complex and tedious.15 Also important to note is that this
nurse was a diligent worker who used to be an honor roll student. Although she
made a fatally grievous mistake and should definitely be held accountable for it,
instances such as these will not be prevented by only punishing her. We need to
accept that even if doctors and nurses are careful and attentive, despite their best
efforts, mistakes will be made. And expectations of perfection from them should
be tempered with a need to design machines and technology that are resistant to
such human errors.
THE EPIDEMIC OF PREVENTABLE DEATHS

A recent publication has put the number of preventable harm that contributes
to hospital deaths at 210,000 to 440,000 annually. This makes it the third largest
killer after heart disease and cancer.16 This is more worrying than the statistics
from 1999 and perhaps is a reflection of the increased numbers as well as
complexity that we see today. The method used in this study is also believed to
be more efficient in collecting these instances than pure physician review as was
done previously. The data was collected from papers published between 2008
and 2011, and possible adverse events were picked up using Global Trigger Tool
(GTT). This was subjected to further scrutiny by physicians who went through
the patient record to ascertain if an adverse event has occurred and to quantify
the harm to the patient. The GRR uses events in the patient record which could
flag an adverse event, such as orders to stop a medication, abnormal lab results or
administration of an antidote such as naloxone. These are then studied in detail
to ascertain if they were preventable. The obvious failing of this method is that it
would only pick up on the errors of commission, and the errors of omission and
indeed unreported events would still be under the radar. This leads the policy
makers to believe that these numbers, horrific though they may be, still grossly
underestimate the actual number of preventable perioperative morbidity or
mortality in patients. In studying the progression of an error to an adverse event
to eventual patient fatality, the cascade effect is also evident. Often a single error
goes undetected and does not cause significant harm, it is often the multiple
small errors which add up and get synergistically magnified that result in a patient
death.17 To quote the author of this paper, “A ‘perfect storm’ of unrecognized but
correctable medical errors can result in serious harm or death”.
In healthcare, we have achieved the pinnacle of technical skill, expertise and
cutting edge scientific know how. The sheer pace and complexity of this field has
grown to such an extent, that now it is the need of the hour to ensure that these
skills benefit our patients to the fullest extent and not be compromised by the
human frailties of the care givers. Training and dispersal of nontechnical skills is
one of the ways we have to go about it.
CONCLUSION
Preventable hospital deaths and morbidity is currently the third largest cause
of death in the United States, and a significant proportion of these are from
human errors. Although knowledge and expertise is important, possessing good
non-technical skills is important for its proper delivery into patient care. These
skills also help in improving interpersonal interactions in situations of stress and
complexity and also contribute to making the work place environment pleasant
and free from strife. Awareness about these skills and training health care
professionals have become desirable in the current situation.
KEY POINTS
• N ontechnical skills are social and cognitive skills that are needed to complement
technical skills for safe and effective task performance.
• There are established tools used to assess and quantify non-technical skills in healthcare
professionals.
• They help in reducing human errors and preventable hospital deaths.
REFERENCES
1. Catchpole KR, Giddings AEB, Hirst G, Dale T, Peek GJ, De Leval MR. A method for
measuring threats and errors in surgery. Cogn Tech Work. 2008;10:295-304.
2. Gawande A, Zinner M, Studdert D, Brennan T. Analysis of error reported by surgeons
at three teaching hospitals. Surgery. 2003;133(6):614-21.
3. Yule, Flin R, Paterson-Brown S, Maran N. Non-technical skills for surgeons: A review of
the literature. Surgery. 2006;139:140-9.
4. Lingard L, Regehr G, Orser B, Reznick R, Baker R, et al. Evaluation of a preoperative
checklist and team briefing among surgeons, nurses, and anesthesiologists to reduce
failures in communication. Arch Surg. 2008;143:12-7.
5. Flinn R, Fletcher G, McGeorge P, Sutherland A, Patey A. Anesthetists’ attitudes to
teamwork and safety. Anaesthesia. 2003;58:233-42.
6. Flinn R, Patey R, Glavin R, Maran N. Anesthetist’s non-technical skills. Br J Anaesth.
2010;105(1):38-44.
7. Kohn LT, Corrigan JM, Donaldson MS. To err is human: building a safer healthcare
system. Washington DC: National Academy Press, 1999.
8. National Transportation Safety Board, Aircraft Accident Report: United Airlines, Inc.
McDonnel-Douglas DC-8-61, N8082U, Portland, Oregon, December 28, 1978, NTSB-
AAR-79-7 (Washington, DC: 1979).
9. Reason J. Human error. Cambridge: Cambridge University Press, 1990.
10. van Klei WA, Hoff RG, van Aarnhem EEHL, et al. Effects of the Introduction of the
WHO “Surgical Safety Checklist” on In-Hospital Mortality: A Cohort Study. Annals of
Surgery. 2012;255(1):44-9.
11. Kothari G, Agrawal J. Color-coded syringe labels: a modification to enhance patient

safety. Br J Anaesth. 2003;110(6):1056-8.
12. Wilson I, Walker I. The WHO surgical safety checklist: the evidence. The Journal of
Perioperative Practice. 2009;19(10):362-4.
13. Vicente K. The human factor—revolutionizing the way people live with technology.
Alfred A Knopf. Canada, 2003.
14. Vicente KJ, Kada-Bekhaled K, Hillel G, Cassano A, Orser BA. Programming errors
contribute to death from patient controlled Analgesia: Case Report and estimate of
probability. Can J Anesth. 2003;50(4):328-32.
15. Emergency care research institute, patient controlled analgesic infusion pumps,
Health Devices. 2001;30:172.
16. James JT. A new, evidence-based estimate of patient harms associated with hospital
care. Journal of Patient Safety. 2013;9(3):122-8.
17. James JT. A sea of broken hearts—patient rights in a dangerous, profit-driven health
care system. Bloomington, In: Author House.
CHAPTER 13
Enhanced Recovery After Surgery
Ashok K Sethi, Anjali Kochhar, Zainab Ahmad
INTRODUCTION
The concept of enhanced recovery (ER) also known as “fast track” or “accelerated
recovery” gained traction in the early 1990s when Henrik Kehlet first proposed the
concept of “stress free anesthesia and surgery” by modulation of the perioperative
stress response by regional anesthetic techniques.1
Later, Kehlet discussed a set of steps for patients undergoing elective colorectal
surgery with the aim to decrease perioperative complications and length of stay.2
These steps later on took the shape of ER protocols.
Enhanced recovery protocols or “fast track” programs are evidence based care
bundles that have a salutary effect on postoperative recovery. These protocols
include preoperative, intraoperative and postoperative components. The safety
and efficacy of ER protocols has been established in multiple randomized
controlled trials and meta-analyses,3-5 including a Cochrane review.6
Effective implementation of ER protocols have been shown to facilitate faster
return of gut function, reduced complication rate, resumption of normal activity
by the patient7 translating into reduced length of postoperative hospital stay and
ultimately better patient as well as nurse satisfaction.8 This is achieved not by
‘accelerating discharge’ but rather by achieving an ‘accelerated postoperative
phase’. The mechanism for efficacy of ER is an attenuation of the neuroendocrine
perioperative stress response, maintenance of organ especially cardiopulmonary
function and an accelerated return of gut function.9 Adoption of ER programs has
also resulted in economic savings for the patient as well as for the hospital even
after accounting for the cost involved in setting up an ER program.10
Though a major body of research on ER is with reference to colorectal
surgery, this concept has also been adopted in pancreatic, gastric, urological,
thoracic, vascular and gynecological surgeries. Work is also ongoing for breast
and reconstructive surgery, head and neck cancer, hepatobiliary, and orthopedic
surgery.
COMPONENTS OF ENHANCED RECOVERY PROTOCOLS (FIG. 13.1)

Preoperative
One of the core principles of ER is to ensure that the patient should be in his best
possible physical condition with best possible optimization of chronic illnesses like
diabetes mellitus, hypertension, COPD, coronary artery disease etc. Consultant
Enhanced Recovery After Surgery 153
Fig. 13.1 Components of enhanced recovery
led anesthetic assessment and consultation with other relevant specialties is

warranted at this point.11
Counseling
Preoperative counseling is an integral part of ER with provision of verbal as well as
written communication regarding the procedure and the expected perioperative
course including training for stoma care if planned. Involvement and contribution
of the patient in an ER program is crucial for its success, therefore time should
be taken to allay his concerns. There is evidence to show that counseling helps
the patient to deal with anxiety12 and fatigue and also reduces pain,13 enhances
patient satisfaction and facilitates early recovery and discharge.14
Cessation of Smoking
Smoking has a profound effect on respiratory system physiology (ciliary action,
sputum production) apart from cardiovascular system as well as on wound
healing. It is associated with increased ICU stay and increased length of hospital
stay. A recent meta-analysis concluded that four weeks of abstinence from

smoking reduces respiratory complications and three to four weeks of abstinence
reduces local wound complications. It is therefore recommended that smoking
be stopped at least 4 weeks prior to surgery in order to further the common goal
of ER.15,16
Cessation of Alcohol Abuse

Hazardous use of alcohol has multiple adverse effects including malnutrition,
impaired immunity, poor wound healing, impaired coagulation, cardiomyopathy
as well as arrhythmias. It has been associated with increased postoperative
morbidity including postoperative pulmonary complications. A recent Cochrane
review concluded that ‘intensive alcohol cessation interventions’ do not have an
effect on 30 day mortality rate or length of hospital stay.17 It, however significantly
decreases the postoperative complication rates. Another recent review, however,
found a tendency towards prolonged length of stay and admission to the intensive
care unit in patients who consume alcohol in the preoperative period.18 If
abstinence is not feasible, alcohol withdrawal should be watched for and treated
aggressively in the perioperative phase.
Anemia Correction
Preoperative anemia is associated with postoperative morbidity and mortality (Hb
<11 g/dL in females and <12 g/dL in males). In keeping with the concept of best
possible physical status, it is recommended to look for and treat iron deficiency
in the preoperative period. Correction of anemia helps to avoid adverse effects of
both transfusion and anemia.19
Prehabilitation
A novel concept of ‘prehabilitation’ has been described in context with ER. It
refers to improving the preoperative functional state of a patient by a multimodal
approach involving an appropriate exercise program along with improved
nutrition and education in the preceding 6–8 weeks of major surgery. The rationale
behind the use of preoperative exercise is the improvement in exercise tolerance
and functional capacity of the patient. A recent meta-analysis concluded that
inspiratory muscle training, aerobic activity, and/or resistance training are asso
ciated with reduction of postoperative complications after abdominal surgery
though evidence for association with length of stay was unclear.20 Another
systematic review found that though pain, quality of life, rate of readmission and
nursing home admission were unaffected, ‘prehabilitation doses of more than
500 minutes’ reduced the need for postoperative rehabilitation.21 It has been
suggested that cardiopulmonary exercise testing be used to stratify preoperative
risk and to monitor effect of exercise to help develop a personalized program for
every patient.22
Preoperative Nutrition
Optimization of nutrition is one of the cornerstones of enhanced recovery after
surgery (ERAS) protocols as poor nutrition is a known factor which adversely
affects surgical outcomes especially in cancer surgery. Severe malnutrition,

according to the ESPEN working group, is defined as the presence of at least
one of the following: weight loss more than 10–15% within last 6 months; body
mass index less than 18 kg/m2; subjective global assessment of grade C; or serum
albumin less than 30 g/L (with no evidence of hepatic or renal dysfunction).23 It is
recommended to provide preoperative oral nutrition supplements for 7–10 days
in these subset of patients.24 There is evidence to show that parenteral nutrition
reduces postoperative complications in malnourished patients; however whether
this is applicable in clinical practice is subject to question.25
Immunonutrition (enteral nutrition that is fortified with arginine, glutamine,
omega-3 fatty acids and nucleotides) has recently come into vogue. A recent
Cochrane review concluded that preoperative immunonutrition reduces
complications and length of hospital stay in patients undergoing gastrointestinal
surgery but the evidence in those subset of patients who may need critical care is
equivocal.25 However, there is no consensus on its formulation, duration, timing
dosage and composition.26
Fasting
Not only is traditional overnight preoperative fasting to protect against aspiration
a matter of anxiety and discomfort to the patient, but it also increases the stress
response and contributes to the ongoing catabolic state of the body. Reduced
fasting times are now almost universally recommended (with few exceptions) to
avoid this metabolic effect. The theoretical risk of aspiration with reduced fasting
times does not have any substantive evidence. In adult patients who fast for
2–4 hours, the gastric volumes are lower and pH is higher than in patients fasting
for more than 4 hours. Similarly in children who fast between 2 hours and 4
hours, the gastric pH is higher than in patients with >4 hours fasting. The ASA
has published practice guidelines for preoperative fasting to reduce the risk of
aspiration in elective surgeries for healthy patients and recommends a 2 hour fast
for clear liquids for healthy patients (assuming a 6 hour fast for solids) undergoing
elective surgery which is in line with the concept of enhanced recovery.27
Oral Carbohydrate Preloading

Along with a short period of fasting vis-à-vis overnight fast, oral carbohydrate
preloading attenuates the neuroendocrine stress response, catabolism and
perioperative insulin resistance. It also improves well-being and reduces
postoperative nausea and vomiting.28 Any clear carbohydrate beverage with
approximately 100 g of carbohydrate may be used (for example commercially
available drinks like Polycal Liquid R are considered appropriate, 200 mL of
which provides approximately, 120 g of carbohydrates that is about 494 Kcal).
It is administered the night before surgery and 3 hours prior to surgery. Evidence
in patients with diabetes mellitus is less clear.
Avoidance of Mechanical Bowel Preparation

This was earlier used routinely before colorectal surgery to reduce the fecal
content in the gut. The rationale was to reduce the solid matter and thereby the
risk of infection. This however has adverse effects such as dyselectrolytemia,
dehydration and discomfort. Evidence is also lacking for its purported ability
to reduce infections. Recent systematic reviews and meta-analyses state that
mechanical bowel preparation (MBP) has shown no or little advantage across
all surgical specialties and does have any effect on postoperative morbidity and
mortality and therefore suggested that MBP be abandoned in routine practice.29,30
However, in rectal and in laparoscopic surgeries the evidence is equivocal and
further research is required.
Thromboembolism Prophylaxis
Thromboprophylaxis is a universally accepted component of ER. It is
recommended that all patients undergoing surgery receive prophylaxis as a
part of ER program. A single daily dose of enoxaparin 20 mg is started the night
before surgery (along with compression stockings) and continued for the entire
duration of hospital stay.31 During the surgical procedure intermittent pneumatic
compression device is also recommended. Other authors have recommended
that all patients undergo risk stratification using a screening tool such as
Caprini score.32,33 The risk of bleeding (patient, surgical and anesthetic risk) is
then evaluated and juxtaposed against the risk of venous thromboembolism
(VTE). It is suggested that all patient with a Caprini score >4 receive appropriate
thromboprophylaxis. Patients with low or moderate risk of bleeding should
receive low-molecular-weight heparin (LMWH). Fondaparinux should be used
in patients with a history of heparin induced thrombocytopenia (HIT) or other
contraindications to LMWH. The direct-acting oral anticoagulants, comprising
dabigatran, rivaroxaban and apixaban, may be used in hip or knee arthroplasty.
In patients with high risk of bleeding such as cardiac surgery, neurosurgery and
spine surgery mechanical prophylaxis with IPC and compression stockings along
with early mobilization is recommended.34 It is recommended that patients
undergoing hip or knee arthroplasty, hip fracture surgery, and abdominal/pelvic
cancer surgery should receive a prolonged course of prophylaxis (28–35 days).32
In minimally invasive surgery thrombo-prophylaxis is not indicated unless other
risk factors like obesity, previous VTE or coagulopathy are present.
Antibiotic Prophylaxis
A single preoperative dose of antibiotic covering both aerobic and nonaerobic
pathogens typically 1st generation cephalosporin or amoxicillin-clavulanic
is recommended within 60 minutes of skin incision. Additional doses are
recommended in obesity, prolonged surgery (4 hours) or severe blood loss
(>1500 mL). Longer course of antibiotics are no longer recommended as they are
associated with risk of infections such as with C. difficile.31
Preanesthetic Medication
‘Routine’ sedatives and anxiolytics are no longer warranted. The patients are
shifted to the preoperative area in a wheelchair to promote active mobilization
up to the immediate preoperative period.
Perioperative
Anesthesia Technique
Balanced anesthesia technique with use of short acting opioids (Remifentanil/
Fentanyl) should be used to allow quick recovery. For maintenance of anesthesia,
inhalational agents like sevoflurane/desflurane or intravenous propofol infusion
can be used. Nitrous oxide is best avoided especially in long duration and
laparoscopic surgeries to avoid bowel distention and postoperative nausea
vomiting. There is moderate evidence to suggest intraoperative use of lung
protective ventilation using low tidal volumes (5–7 mL/kg).35 Use of epidural
analgesia for pain relief is ideal especially in open procedures. For laparoscopic
surgeries, uses of epidural needs to be individualized as benefits are less clear.
Surgical Approach
Use of laparoscopic and minimally invasive technique is preferred. For open
procedures, either a transverse or a smaller vertical incision is recommended.
Use of nasogastric tube in the postoperative period does not prevent bowel leak
or wound dehiscence but may lead to complications like pneumonia and is
best avoided. Avoidance of nasogastric tube and abdominal drain helps in early
mobilization of the patients.
High Inspired Oxygen

High inspired oxygen is shown to improve blood flow at the anastomotic site and
reduces risk of wound infections. It helps in enhancing defense against microbes
and improves wound healing. In a review on this topic, it was reported that
administration of 80% FiO2 doubled the subcutaneous tissue oxygen tension and
halved the rate of local infection.36 The authors also reported that supplemental
oxygen had the added benefit of reduced postoperative nausea and vomiting
after open and minimally invasive abdominal surgeries. Supplemental oxygen
administration was not associated with clinically significant side effects. However,
there is lack of consensus on duration and concentration of perioperative oxygen.
Perioperative Fluid Administration

Fluid therapy is an integral part of enhanced recovery program. Goal of fluid
management is to provide optimal circulatory volume (without over/under
hydration) referred to as “zero balance approach’’. Liberal fluid therapy has been
practiced for years for open abdominal surgeries. Recent studies have shown that
excessive fluid administration can be associated with poor healing of intestinal
anastomosis and prolonged ileus.37 Over hydration may lead to rise in central
venous pressure causing pulmonary and peripheral edema. Evidence suggests
that it can increase postoperative morbidity and lengthen the hospital stay after
major abdominal surgery.38
In the intraoperative period, zero balance approach should be maintained.
Fluid therapy should be tailored to blood loss and maintenance requirements.
Hypotension associated with general anesthesia or epidural should be treated
with vasoconstrictors rather than fluids. The reason behind this change is
two-fold, one is the cause of this hypotension, which is vasodilatation and loss of
body’s physiological ability to compensate for it due to effects of anesthesia and

second is the change in practice of prolonged preoperative fasting period. A well
prepared patient with 2 hours fasting will remain euvolemic and well hydrated.
Management of anesthesia induced hypotension using vasoconstrictors is
associated with reduced postoperative complications and length of stay in the
hospital.39 To individualize zero balance approach, use of esophageal Doppler
(which provides real time hemodynamic monitoring) especially in high risk and
elderly patients is recommended. A recent meta-analysis of goal directed fluid
therapy on bowel function after abdominal surgery shows that it facilitates gut
recovery. Though, in the setting of enhanced recovery protocol, its value still
needs to be proven.40 Postoperatively, oral fluids should be initiated as early as
2 hours after surgery with an aim to taper off intravenous fluids by the second
postoperative day. Early feeding reduces anastomotic dehiscence, infection and
length of hospital stay.
A balanced salt solution is the ideal fluid in the perioperative period as normal
saline has been associated with sodium load, hyperchloremia, metabolic acidosis
and poor outcomes. Indications and role of colloid therapy are not very clear in
the context of enhanced recovery.
Prevention of Hypothermia
Hypothermia is a common problem encountered in open abdominal procedures
due to altered physiological mechanisms of thermoregulation under the effects
of general as well as regional anesthesia and rapid infusion of intravenous fluids.
Hypothermia not only alters drug metabolism but also impairs immunity and
has adverse effects on coagulation and cardiovascular system. Studies show
that hypothermia can lead to increased metabolic demand, cardiovascular
complications, wound infection and increased demand for blood transfusion.
Preventive measures include monitoring of temperature throughout the peri-
operative period using esophageal probe to monitor core temperature, use of
passive as well as active warming techniques. Use of several layers of drapes and
fluid air warming systems along with warming of intravenous fluids can be used
in sync to maintain normothermia.
Nausea and Vomiting Prophylaxis

Incidence of nausea and vomiting ranges from 10% to 20% in fast-track surgeries.
Nausea and vomiting not only causes significant patient dissatisfaction but can
also result in higher risk of aspiration and bowel dehiscence. Guidelines with
respect to management of nausea and vomiting are clear. All patients with a
moderate or high risk of PONV (as per Apfel risk score) should be given prophy-
lactic antiemetics. Patients at moderate risk should be given either intravenous
dexamethasone after the induction of anesthesia or a 5-HT3 antagonist
(e.g. Ondansetron) before the completion of surgery. High risk patients require
administration of two antiemetics during anesthesia (dexamethasone and a
5-HT3 antagonist, metoclopramide or droperidol). Total intravenous anesthesia
with propofol, should also be considered instead of volatile anesthetics.
Postoperative
Postoperative Analgesia
Multimodal analgesic approach is the cornerstone of pain management. Goal
of multimodal approach is to enhance pain relief and reduce the side effects
of individual drugs particularly opioids. Opioids although very effective in
pain relief, have been associated with nausea, vomiting, gut dysfunction,
respiratory depression, drowsiness and hence, prolonged hospital stay. Recent
Polish guidelines41 (2014) also lay emphasis on preemptive analgesia to modify
nociception. Use of epidural analgesia is advocated for open colorectal surgery.
Intraoperative thoracic epidural analgesia and analgesia is beneficial as it is
shown to enhance colonic blood flow.42 Epidural anesthesia not only reduces
the stress response associated with surgery but also restores bowel activity and
shortens hospital stay. A recent meta-analysis states that epidural anesthesia may
be associated with superior pain control but this does not translate into improved
recovery or reduced morbidity when compared with alternative analgesic
techniques when used within an enhanced recovery protocol. It is advisable
to remove epidural catheter on second postoperative day to enhance patient
mobilization. Use of paracetamol and NSAID’s both during and after surgery
reduces dose of opioids as well as helps in management of pain after the removal
of epidural catheter.
Local wound infiltration or continuous infusion of local anesthetics using
wound pumps has been used and found to be as efficient as epidurals in reducing
pain in the first 48 hours postoperatively, with lower rates of urinary retention.
Recently transverse abdominal plane (TAP blocks) has become popular as an
alternate option to wound infiltration or epidural analgesia.
Postoperative Glycemic Control

Hyperglycemia (blood sugar >180–200 mg/dL) is commonly observed in the
postoperative period. It has shown to adversely affect postoperative outcome
in terms of infection, length of hospital stay including increased mortality rates.
Target blood sugar should be between 180 mg/dL–200 mg/dL and patients
having blood glucose higher than this range should be treated with insulin
therapy. It is recommended to do regular blood glucose monitoring to prevent
iatrogenic hypoglycemia.
Early Postoperative Mobilization

There should be planned early mobilization with the involvement of physio
therapist with an aim to make the patient sit on chair same evening or the very first
day of surgery. Avoidance of abdominal drains, nasogastric tubes and opioids can
help in early mobilization. Early mobilization reduces risk of thromboembolic
and pulmonary complications.
Early Enteral Diet

Postoperatively patients are likely to develop ileus secondary to intraoperative
bowel handling, use of opioids, excessive crystalloids and surgical stress. Early
feeding by enteral route is shown to minimize postoperative insulin resistance,
hyperglycemia, nitrogen loss and enhances recovery. There is no benefit in

keeping the patients nil oral postoperatively.43 Chewing gum and laxatives
have been used as a measure to enhance gut recovery as it reduces the time to
pass flatus. Bowel sounds are not reliable in predicting start of enteral feeding.
Oral fluids should be started as early as 2 hours postoperatively and increased
as tolerated by the patient. Oral intake of a single high calorie carbohydrate or
protein drink is encouraged.
Early Discharge
Patients are usually ready to go home in 8–9 days following major abdominal
surgery. Major concerns are anastomotic leak and stoma independence.
With implementation of enhanced recovery program patients can be sent home in
4–5 days. Poor ASA grade, old age, postoperative opioid use, rectal and complex
surgical procedures are some of the predictors of delayed discharge.44,45
IMPLEMENTATION
A multidisciplinary team approach is mandatory to facilitate the establishment of
an ER program. Regular audits to evaluate rate of compliance, rates of complication
and of readmission must be carried out. Readmission is an important marker of
quality and should be <10%.
CONCLUSION
The concept of enhanced recovery is safe and effective. Preoperative, peri
operative and postoperative components of enhanced recovery should be used to
promote early recovery in patients undergoing surgery. Implementation of such
a program involves multidisciplinary effort and gradual evolution and adoption
of evidence based best practices.
KEY POINTS
• E nhanced recovery protocols are evidence based care bundles that have a salutary
effect on postoperative recovery.
• These protocols include preoperative, perioperative and postoperative components.
• Enhanced recovery is facilitated by achieving an accelerated postoperative phase.
• The mechanism for efficacy of enhanced recovery is an attenuation of the neuro-
endocrine perioperative stress response along with maintenance of organ function.
• Adoption of enhanced recovery results in reduced complications, faster resumption of
activity, reduced length of stay and improved patient satisfaction.
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36. Kabon B, Kurz A. Optimal perioperative oxygen administration. Curr Opin
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CHAPTER 14
Pharmacokinetics in Obstetric Patients
Lakshmanan Parthasarathy, Naheed Azhar
INTRODUCTION
During pregnancy, a woman undergoes significant changes in anatomy,
physiology, hormonal and biochemical processes, which affect every aspect of
the pharmacokinetics of administered drugs.1 The maternal-placental-fetal unit
can suffer from both the direct and indirect effects of administered drugs due
to changes in placental and uterine function. Maternal drugs can be transferred
across the placenta affecting the newborn. Even after delivery, it may continue
to be secreted in the breast milk, which will again affect the baby. Knowledge
of pharmacokinetics in obstetric patients can guide the obstetric anesthetist
in finding the right balance between risks and benefits of a therapy to both the
mother and baby. Only proven safe drugs must be used in the pregnant patient,
but the adverse effects of many drugs is uncertain. The American Society of
Anesthesiologists has established guidelines and protocols for providing safe
care during obstetric anesthesia.2
PHARMACOKINETIC CHANGES
Pregnancy affects every aspect of the pharmacokinetics of drugs.3 The response
to the maternal and fetal exposure of drugs is influenced by changes in maternal
pharmacokinetics due to pregnancy induced changes in physiology, amount
of drug crossing the placenta and the influence of the fetus on the distribution,
metabolism and elimination of the drug.
Absorption and Uptake

Intestinal motility decreases in pregnancy leading to an increased
gastrointestinal (GI) transit time by 30–50%. However, during labor and after
administration of opioids, the gastric emptying may be delayed. There is an
increase in gastric pH, which affects absorption of drugs that are weak acids
and bases. Clinically, the changes in bioavailability of a drug during pregnancy
are very small. An increase in CO by 30–50% and an increased blood flow to
skin and mucous membranes can enhance drug absorption from these sites.
Reduced functional residual capacity (FRC) and increased alveolar ventilation
by 70% favors alveolar uptake of inhalational anesthetics.4
Pharmacokinetics in Obstetric Patients 165
Distribution
Pregnancy is accompanied with increased CO and hyperdynamic circulation
that increases the distribution of all drugs across the body. The drugs will be
delivered more rapidly to the peripheral target tissue sites. This increase in
peripheral perfusion however will lead to a delay in arterial and brain anesthetic
concentration.
Total body water during pregnancy, increases by 8 L and plasma volume by
55%.5 The larger volume of distribution (Vd) decreases the peak concentration
of hydrophilic drugs necessitating higher initial dose. Body fat content during
pregnancy increases by 4 kg.6 But this is unimportant due to the very large volume
of distribution for lipophilic drugs. Lipophilic anesthetic agents like thiopentone
and bupivacaine tend to distribute and be held in this large adipose tissue depot
leading to persistently high drug concentration.
Protein Binding
All anesthetic drugs bind to plasma proteins either albumin or a-1-glycoprotein
(AAG). Albumin binds to weak acidic and/or lipophilic drugs while AAG binds to
basic drugs. Serum albumin drops by 70% from non-pregnant levels of 4.5 g/dL
to 3.9 g/dL in the 1st trimester, 3.6 g/dL in the 2nd trimester and touching a low of
3.3 g/dL in the 3rd trimester. Hence, protein binding of these drugs is decreased
during pregnancy.7 This decrease in albumin also decreases the colloid oncotic
pressure during the same periods from 27 to 25 and at term to a low of 22 mm
Hg. While the concentration of free drug is increased, in chronic drug therapy,
the increased drug clearance offsets this change. The increase in free fatty acids,
placental and steroidal hormones during pregnancy at term displaces drugs
from their albumin binding sites compounding the problem further. Decreased
protein binding makes more free drug available for producing an effect and at the
same time more free drug is also available for metabolism and elimination.
Alpha-1-glycoprotein is an acute phase protein and remains constant
throughout pregnancy.8
Metabolism
During pregnancy, CO is increased leading to an increase in hepatic blood flow
and in hepatic clearance. The drugs dependent on hepatic clearance includes
lignocaine and morphine. Oxidation and conjugation processes of hepatic
metabolism may also be affected during pregnancy. Hepatic enzymatic activity of
cytochrome P450 (CYP450) system involved in phase 1 reactions, is also affected.
Phase 1 isoenzymes like CYP3A4, CYP2D6, CYP2C9 and phase 2 UGT isoenzymes
like UGT1A4 and UGT2B7 have increases enzymatic activity during pregnancy.
This increases the metabolism of drugs like phenytoin, midazolam, morphine
and NSAID.9 Other isoenzymes like CYP1A2 and CYP2C19 have decreased and
so, this can reduce the metabolism of drugs like caffeine and theophylline. Hence,
dugs metabolized by liver will need increase or decrease in dose depending on
the metabolic pathways involved.
Elimination
During pregnancy, the renal blood flow increases by 60–80% and glomerular
filtration rate (GFR) increase by 50% due to reduced renal vascular resistance.10
Drugs that are excreted unchanged by the kidney like cephalosporin antibiotics,
digoxin and lithium may require an increase in dose by 20–65%.
Increased minute ventilation hastens the elimination of inhaled anesthetics.
PLACENTAL DRUG TRANSFER

Drugs given to the pregnant mother freely cross the placenta in the unbound
and nonionized form. The factors controlling placental transfer of drugs include
concentration gradient of the unbound nonionized drug across the membrane,
placental blood flow and duration of exposure.11 The fetus has slightly higher
concentrations of albumin and one-third the concentration of AAG when
compared to maternal values. Fetal pH is also lower than the maternal pH
and basic drugs like opioids and local anesthetics cross the placenta, become
more ionized in the fetus and are unable to transfer back across the placenta
to maternal side. This phenomenon of “ion trapping” is relevant in a scenario
of severe fetal acidosis. The fetus and neonate metabolize drugs, but a reduced
rate compared to adults. Nitrogen oxide (N2O) significantly crosses the placental
barrier during anesthesia, but its poor lipid solubility ensures that there is no
significant accumulation in the fetus.12
PHARMACOKINETICS OF COMMON ANESTHETIC DRUGS

DURING PREGNANCY
Inhalational Anesthetics
Volatile agents decrease uteroplacental blood flow due to hypotension and
uterine tone. Volatile agents rapidly cross the placenta and can depress
frequency, amplitude and duration of uterine contractions, completely inhibiting
them at 2 minimum alveolar concentration (2MAC). This reduction of effect
of oxytocin on uterine tone by volatile agents may lead to greater blood loss
after delivery. The MAC value for inhalational agents has been demonstrated
to be lower in several animal and human studies. The reduced requirements
during pregnancy may be due to the effect of progesterone and increased
endogenous endorphins that mediate the increase in nociceptive threshold
during pregnancy. The MAC requirement of inhalational agents is reduced by
25–40% during pregnancy.13 Inhalational induction is faster during pregnancy
due to increased minute ventilation and decreased FRC. This faster induction
is achieved in spite of the increased cardiac output that tends to counter it.
Using transcutaneous electrical stimulation, isoflurane MAC was found to be
decreased by 28%. Similar reductions were recorded for halothane and enflurane
in the immediate postpartum period. The values returned to normal within
72 hours after delivery. Sevoflurane concentration during 2nd trimester to achieve
a targeted BIS of 50 was reduced by 31%. The median MAC awake concentration
of N2O during pregnancy was reduced by 25–27%. Newer inhalational agents
like sevoflurane and desflurane have been found to be safe to use in obstetric
patients. It has been recommended that a minimum of 0.75 MAC of inhalational
agent needs to be combined with 50% N2O to prevent awareness and maintain
BIS values less than 60.14
Nitrous oxide has minimal effect on uterine tone. When used with 50% O2 and
no volatiles, it is associated with awareness in 12–26% patients. It readily crosses
the placenta and has a UV/MV ratio of 0.37 at 2–9 minutes. It does not adversely
affect Apgar scores or neurological behavior of newborns. Use of N2O allows us to
reduce the concentration of more potent inhalational agents.
Several recent studies in animal models have indicated that general anes
thetics may have toxic effects on the developing brain leading to neuroapoptosis,
permanent neuropathological changes and long-term neurobehavioral changes.15
Intravenous Anesthetics
The reduction in requirement of IV anesthetics (8–18%) is lesser than the
reduction in MAC values of inhalational agents (30%).
Thiopentone dose for hypnosis (loss of eyelash reflex) is reduced by 17% and
that for anesthesia (response to transcutaneous electrical stimulus) is reduced
by 18% during pregnancy. The safety of thiopentone for induction of anesthesia
has been accepted across all gestational ages. The induction dose of thiopentone
in parturient may be decreased by up to 35%. The elimination half-life of the
drug is prolonged during pregnancy to 26 hours versus 11 hours in non-pregnant
women. Thiopentone is used in an induction dose of 4 mg/kg readily crosses the
placenta. It has an umbilical artery to vein (UA/UV) ratio of 0.87 and equilibrated
rapidly in fetal blood.16 Neonatal depression however does not occur because
the fetal brain concentration never reaches the critical threshold values needed
for depression. Several explanations have been offered to explain why a mother
asleep under thiopentone delivers an awake baby. The higher water content of
the fetal brain, rapid uptake and first pass metabolism by fetal liver and rapid
redistribution of drug in maternal tissues are some of the possible explanation.
This depression can occur, if abnormally high doses of thiopentone (8 mg/kg) are
used.17
Propofol pharmacokinetics, requirements, half-life are unaltered in
pregnancy except for a more rapid clearance. The UV/MV ratio of propofol is
0.7.18 Propofol when used in higher doses can produce neurologically depressed
babies at birth. Propofol produces more severe maternal hypotension when
compared to thiopentone when used for induction. The incidence of awareness
has been documented to be more during propofol anesthesia when compared to
thiopentone. During pregnancy, propofol does not offer any significant advantage
over thiopentone for induction of anesthesia.
Ketamine is an ideal induction agent for pregnant patients who are hypo-
volemic or asthmatics. The sympathomimetic induced increase in blood pressure
(BP) produced by ketamine while advantageous in a hypotensive patient is
contraindicated in a patient with pregnancy-induced hypertension (PIH).
Ketamine produces a dose dependent increase in uterine tone. Ketamine crosses
the placental barrier freely and has a UV/MV ratio of 0.04–0.5, making it safe for
the fetus. When used in higher doses it produces lower Apgar score and muscular
hypertonicity in the newborn.19
Etomidate at 0.3 mg/kg is ideally suited for induction in hemodynamically
unstable pregnant patients and those with severe cardiac disease. It has a UV/MV
ratio of 0.04–0.5 and is safe for the fetus.20 When etomidate is used, a transient
decrease in neonatal serum cortisol has been documented. This however has not
been associated with any clinical relevance.
Neuromuscular Blockers
Muscle relaxants are larger molecules, highly ionized with low lipid solubility
and hence do not cross the placental barrier easily. They can be safely used in
pregnant women and do not adversely affect the newborn.
Succinylcholine is the preferred relaxant for rapid sequence induction of
general anesthesia. In clinical doses, very little drug is transferred to the fetus.
Although serum pseudocholinesterase levels are decreased during pregnancy,
the twitch height recovery of succinylcholine is unchanged during pregnancy. At
term, the pseudocholinesterase activity is decreased by 24% and returns to normal
2–6 weeks postpartum. Metoclopramide administration inhibits activity of this
enzyme.21 However, the larger volume of distribution during pregnancy ensures
fast recovery and does not produce any change in duration or metabolism of the
drug.
Rocuronium is an excellent alternative for rapid sequence induction. It is used
in a dose of 0.6 mg/kg enabling intubation at 90 seconds and with no adverse
effect on the fetus.
Vecuronium in a dose of 0.1 mg/kg has a significantly slow onset of action.
In spite of pregnancy producing increased clearance and shortened half-life,
parturient demonstrate an increased sensitivity to vecuronium. It crosses
placental barrier in minute quantities but does not adversely affect the fetus.22
Atracurium has slow onset and is associated with significant histamine
release. When used in intubating doses, it can produce significant hypotension.
The pharmacokinetics and pharmacodynamics of atracurium are unaltered
during pregnancy.
Cisatracurium has decreased histamine release and it is hampered by slower
onset and shorter duration of action.23
Analgesics
The nociceptive response thresholds mediated by the endogenous opioid
systems are increased during pregnancy. This change is probably due to the effect
of progesterone and estrogen, and appears to involve the spinal cord kappa and
delta opioid receptors, and the alpha 2 non-adrenergic pathways. Opioids cross
the placental barrier and dose dependent fetal depression. Therefore, it is safer
to withhold maternal administration of systemic opioids until the delivery of the
fetus. If a strong requirement for maternal systemic opioids exists before delivery
it may be prudent to avoid morphine, pethidine and also fentanyl. Morphine and
pethidine administration produced reductions in beat-to-beat variability and
incidences of acceleration. Short-acting opioids like remifentanil are preferred
over alfentanil. Maternal remifentanil in a dose of 1 µg/kg before delivery
produced nonreactive fetal heart traces and normal Apgar score.24 However,
other studies have shown conflicting results.
When narcotics are used as part of central neuraxial blocks, the doses
administered and the maternal levels achieved are so low that they do not affect
the fetus. Long duration epidural infusions of local anesthetic and epidural
opioid combination in a pregnant mother who lands up for emergency lower
segment cesarean section (LSCS) may have enough maternal levels of opioid to
depress the fetus. Pregnant patients on long duration infusions must not receive
any further dose of opioids until after delivery.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Cyclo-oxygenase inhibitors can cause premature closure of ductus arteriosus and
produce increased pulmonary vascular resistance. They also decrease fetal renal
perfusion and decrease fetal urinary output and can produce oligohydramnios.
Aspirin is not associated with any congenital malformation but its use may be
associated with increased blood loss during delivery. Paracetamol is safe for use
during pregnancy.25
Vasopressors and Chronotropic Agents

The response to vasopressors and inotropes is reduced during pregnancy due
to the down-regulation of beta-adrenergic receptors. These agents may be less
sensitive markers of intravascular injection as part of test dose while initiating
neuraxial anesthesia. The vasopressor of choice to treat hypotension due to
neuraxial blockade has traditionally been ephedrine. Ephedrine was considered
to the best drug to preserve the uteroplacental blood flow. Recent evidence has
shown that ephedrine depresses fetal pH and base excess when compared to other
agents.26 Ephedrine more readily crosses the placenta then phenylephrine and
produces higher concentrations of catecholamines, glucose and lactate. These
direct effects on fetal metabolism have been postulated as reasons for adverse
changes in fetal pH.27 Recent literature supports the use of alpha adrenergic
agonists like phenylephrine and metaraminol for treating hypotension during
LSCS. Several recent studies have concluded that to optimize fetal acid base
status, large doses of ephedrine should be avoided and alpha adrenergic agonists
must be the first line agents to treat hypotension. Phenylephrine in boluses of
50–100 µg or as an infusion at 25–100 µg/min is recommended to maintain blood
pressure during LSCS under spinal anesthesia.
Local Anesthetics
Pregnant women have an increased spread of neuraxial block starting as early
as 1st trimester leading to more rapid onset and longer duration. The median
effective dose of intrathecal bupivacaine decreases by 13–35% at term.28 Pregnant
women have decreased spinal cerebrospinal fluid (CSF) volume, distended
vertebral venous plexus, increased neural sensitivity, and increased rostral
spread. These mechanical factors contribute to the increased degree of blocks.
The increased sensitivity of neuronal tissue to local anesthetics is probably
influenced by progesterone which facilitates easier diffusion of local anaesthetic
and/or an interaction with endogenous analgesic systems. The dose of local
anesthetics (LA) in spine is too small to produce any significant effect on the fetus.
In epidurals, significant fetal concentrations of LA can be achieved especially in a
situation of accidental intravascular injection.
Bupivacine and lignocaine bind to alpha-1 acid glycoprotein which is
more in maternal than fetal blood. Bupivacaine also binds with low affinity to
albumin. Hence, the protein binding of these drugs may be decreased during
pregnancy. The fetal: maternal ratio of bupivacaine is 0.2–0.4 and for lignocaine is
0.5–0.7.29 Lignocaine and bupivacaine are weak bases and in the presence of
fetal asphyxia and acidosis, “ion trapping” of the local anesthetic molecules can
occur in the fetal tissues. Ropivacaine pharmacokinetics are little affected in
parturient.30
EFFECT OF ANESTHETIC DRUGS ON DEVELOPING FETUS

The incidence of nonobstetric surgery in pregnant women is 0.5–2%. The
concerns in such surgery are the teratogenicity of anesthetic drugs and risk of
preterm labor and delivery of the fetus. Drugs during such situations must be
used only when necessary with the minimum effective dose being used. The risk-
benefit ratio must justify the use of a particular drug.
The established period of teratogenicity is during the period of organogenesis.
This occurs between 2½ to 8 weeks after conception (Fig. 14.1).
In 1979, the US FDA introduced a risk classification system to categorize
drugs according to their risk potential.31
Fig. 14.1 Fetal development and period of teratogenicity

Abbreviations: CNS, central nervous system; LMP, last menstrual period
Category A: “No Risk”

• Well controlled human studies have demonstrated no risk to the fetus.
• No anesthetic drug exists in category A.
Category B: “No Evidence of Risk in Humans”

Animal studies have found a risk but human studies have not. Animal studies are
negative but adequate human studies have not been done. The anesthetic drugs
in category B are:
• Induction agents: Propofol, methohexital
• Inhalational: Sevoflurane, desflurane, enflurane
• Opioids: Meperidine
• Neuromuscular blockers: Rocuronium, cis-atracurium
• Local anesthetics: Ropivacaine, lignocaine.
Category C: “Risk cannot be Ruled Out”

Animal studies are positive but human studies have not been conducted or
adequately performed. These drugs must be used only if potential benefit
outweighs the risk to the fetus. The anesthetic drugs in category C are:
• Induction agents: Thiopentone, ketamine, etomidate
• Inhalationals: Halothane, isoflurane
• Opioids: Morphine, fentanil, alfentanil, sufentanil
• Neuromuscular blockers: Succinylcholine, vecuronium, atracurium,
pancuronium, mivacurium, curare
• Local anesthetics: Bupivacaine, 2-chloroprocaine, tetracaine.
Category D: “Potential Evidence of Risk”

There is confirmed evidence of human risk. In spite of the risks, it is used if no
other medication is available to treat a life-threatening situation. The anesthetic
drugs in category D are:
• Benzodiazepines: Diazepam, midazolam.
Category X: “Contraindicated in Pregnancy”

• Human and animal studies show definitive fetal risk which outweighs any
potential benefit to the patient.
• There are no anesthetic drugs in category X.
• The drugs that are definitively known to be teratogenic include alcohol,
androgens, antithyroid drugs, carbamazepine, chemotherapy agents, cocaine,
warfarin, lithium, angiotensin-converting enzyme inhibitor (ACEI), valproic
acid, phenytoin, streptomycin, tetracycline, thalidomide, trimethadione and
diethylstilbestrol.
NITROUS OXIDE AND SAFETY IN PREGNANCY

Nitrous oxide is a teratogen in animal studies and readily crosses the placenta.
Teratogenicity of N2O is thought to be caused by its blocking the co-factor to
enzyme methionine synthetase, which is needed to produce thymidine subunit
of DNA. There is no clinical evidence to conclusively support this hypothesis and

pretreatment with folinic acid does not reduce the incidence of fetal abnormalities.
The concerns regarding the use of N2O in pregnant women is largely theoretical
and no human studies have proved that administration of N2O is associated with
increased incidence of chromosomal abnormalities.32
CONCLUSION
Fetus receives a portion of all drugs given to the mother and can alter the fetal
development or the neonatal behavior. Therefore, one must be aware of the
pharmacokinetic, pharmacodynamics and the teratogenic potential of the drugs
administered during pregnancy.
KEY POINTS
• M aternal-placental-fetal unit can suffer from both the direct and indirect effects of
administered drugs due to changes in placental and uterine function.
• Transfer of drugs across the placenta is affected by the concentration gradient, placental
blood flow and duration of exposure.
• MAC of inhaled and intravenous anesthetics is reduced by 25–40% during pregnancy.
• Muscle relaxants are highly ionised and do not cross the placenta.
• Opioids cross the placenta and cause dose dependant fetal depression.
• Knowledge of pharmacokinetics in obstetric patients can guide the obstetric
anesthesiologist in finding the right balance between risks and benefits of a therapy
both to the mother and baby.
• Only proven safe drugs should be administered to pregnant women.
REFERENCES
1. Hutson JR, Leiger C, Koren G. Pharmacokinetics in pregnancy. In: Yehuda Ginosar
et al. (eds). Anesthesia and the Fetus, 1st edition, Wiley-Blackwell Publication; 2013.
pp.53-60
2. Toledano RD, Kodali B, et al. Anaesthesia drugs in obstetric and gynecologic practice:
Reviews in obstetric and gynecology; 2009;2(2):93-100.
3. Chiloiro M, Darconza G, et al. Gastric emptying and orocecal transit time in pregnancy.
J Gastroenterol. 2001;36:538-43.
4. Wise RA, Polito AJ, et al. Respiratory physiologic changes in pregnancy. Immunol
allergy. Clin North Am. 2006;26:1-12.
5. Gaiser R. Physiologic changes in pregnancy. In: David H Chestnut, et al. Chestnut’s
Obstetric Anesthesia: Principles and Practice, 4th edition, Mosby Elsevier publication;
2009.pp.15-30.
6. Spatling L, Fallenstein F, et al. The variability of cardiopulmonary adaptation to
pregnancy at rest and during exercise. Br J Obstet Gynaecol. 1992;99(Suppl 8):1-40.
7. Krauer B, Dayer P, et al. Changes in serum albumin and alpha1-acid glycoprotein
concentrations during pregnancy: an analysis of feto-maternal pairs. Br J Obstet
Gynaecol. 1984;91:875-81.
8. Porter JM, Kelleher N, Flynn R, et al. Epidural ropivacaine hydrochloride during
labour: protein binding, placental transfer and neonatal outcome. Anaesthesia. 2001;
56:418-23.
9. Anderson GD. Pregnancy induced changes in pharmacokinetics: a mechanistic based
approach. Clin Pharmacokinet. 2005;44:998-1008.
10. Davison JM, Hytten FE. Glomerular filtration during and after pregnancy. J Obstet
Gynaecol Br Commons. 1974;81:588-95.
11. Pickering B, Biehl D, Meatherall R. The effect of fetal acidosis on bupivacaine levels in
utero. Can Anaesth Soc J. 1981;28:544-9.
12. Karasawa F, Takita A, Fukuda I, et al. Nitrous oxide concentrations in maternal and fetal
blood during caesarean section. Eur J Anaesthesiol. 2003;20:555-9.
13. Palahniuk RJ, Shnider SM, Eger EI. Pregnancy decreases the requirement for inhaled
anaesthetic agents. Anaesthesiology. 1974;41:82-3.
14. Chin KJ, Yeo SW. A BIS-guided study of sevoflurane requirements for adequate depth
of anaesthesia in caesarean section. Anaesthesia. 2004;59:1064-8.
15. Brambrink AM, Evers AS, Avidan MS, et al. Isoflurane induced neuroapoptosis in the
neonatal rhesus macaque brain. Anesthesiology. 2010;112:834-41
16. Morgan DJ, Blackman GL, Paull GD, et al. Pharmacokinetics and plasma binding of
thiopental II: studies at caesarean section. Anesthesiology. 1981;54:474-80.
17. Finster M,Morishima HO, Mark LC, et al. Tissue thiopental concentrations in the fetus
and newborn. Anaesthesiology. 1972;36:155-8.
18. Gin T, Gregory MA, Chan K, et al. Pharmacokinetics of propofol in women undergoing
elective caesarean section. Br J Anaesth. 1990;64:148-53.
19. Downing JW, Mahomedy MC, Jeal DE, et al. Anaesthesia for caesarean section with
ketamine. Anaesthesia. 1976;31:883-92.
20. Downing JW, Buley RJ, Brock-Utne JG, et al. Etomidate for induction of anaesthesia at
caesarean section: comparison with thiopentone. Br J Anaesth. 1979;51:135-40.
21. Kao YJ, Turner DR. Prolongation of succinylcholine block by metoclopramide.
22. Margorian T, Flannery KB, Miller RD. Comparison of rocuronium, succinylcholine
and vecuronium for rapid-sequence induction of anesthesia in adult patients.
23. Eikermann M, Peters J. Nerve stimulation at 0.15 Hz when compared to 0.1 Hz speeds
the onset action of cisatracurium and rocuronium. Acta Anaesthesiol Scand. 2000;
44:170-4.
24. Douma MR, Verwey RA, Kim-Endtz CE, et al. Obstetric analgesia: a comparison of
patient controlled meperidine, remifentanil, and fentanyl in labour. Br J Anaesth. 2010;
104:209-15.
25. Shalini M, Sonali K. Safety of analgesics in pregnancy. International Journal of
Obstetrics and Gynaecology Research. 2016;3(1):208-12.
26. Lee A, Ngan Kee WD, Gin T. A quantitative systematic review of randomized controlled
trials of ephedrine versus phenylephrine for the management of hypotension during
spinal anaesthesia for caesarean delivery. Anesth Analg. 2002;94:920-6.
27. Ngan Kee WD, Khaw KS, Tan PE, et al. Placental transfer and fetal metabolic effects
of phenylephrine and ephedrine during spinal anaesthesia for caesarean delivery.
Anaesthesiology. 2009;111:506-12.
28. Hirabayashi Y, Shimizu R, Fukuda H, et al. Spread of subarachnoid hyperbaric
amethocaine in pregnant women. Br J Anaesth. 1995;74:384-6.
29. Biehl D, Shnider SM, Levinson G, et al. Placental transfer of lidocaine: effect of fetal
acidosis. Anesthesiology. 1978;48:409-12.
30. Santos AC, DeArmas PI. Systemic toxicity of levobupivacaine, bupivacaine and
ropivacaine during continuous intravenous infusion to nonpregnant and pregnant
ewes. Anaesthesiology. 2001;95:1256-64.
31. Hemminki K, Kyyronen P, Lindbohm ML. Spontaneous abortions and malformations
in the offspring of nurses exposed to anaesthetic gases, cytostatic drugs, and other
potential hazards in hospitals, based on registered information of outcome. J Epidemiol
Community Health. 1985;39:141-7.
32. Rowland AS, Baird DD, Shore DL, Weinberg CR, Savitz DA, Wilcox AJ. Nitrous oxide
and spontaneous abortion in female dental assistants. Am J Epidemiol. 1995;141:
531-8.
CHAPTER 15
Opioid-induced Hyperalgesia
Pramod Kohli
INTRODUCTION
Opioids have since long been the mainstay of acute surgical and nonsurgical
pain management and palliation of terminal cancer pain. Since the past few
decades they have also been successfully used for management of chronic
neuropathic pain. Chronic administration of opioids is associated with the well-
known side effects of dependence and tolerance. Lately another phenomenon,
the ‘opioid-induced hyperalgesia’ (OIH) has been recognized and is causing
great concern.
Opioid-induced hyperalgesia has been defined as “a state of nociceptive
sensitization caused by exposure to opioids”.1 It is thus a condition in which
the opioids despite initial pain relief, cause subsequent enhanced pain. This
enhanced pain may retain the nature of pre-existent pain or may even be different
in character.2,3
HISTORICAL CONSIDERATIONS
Opioid-induced was probably recognized as early as 1870 when Albutt4 reported
that morphine, though a potent analgesic, could result in increased pain. This
was further supported by the observations of Rossbach, who in 1880, noted that
once ‘dependence’ on opioids is established, they have an opposite effect.1 More
recently, hyperalgesia or ‘pain intolerance’ has been reported in opioid addicts
and also in patients on long-term opioid maintenance.5,6 After almost a century,
interest in the entity was rekindled, and since 1970s, there have been many
reports of its presence in murine experiments. Human volunteer experiments
and clinical trials have followed to understand and overcome OIH.
OPIOID-INDUCED HYPERALGESIA AND OPIOID TOLERANCE

Clinical presentation of both opioid tolerance and opioid-induced hyperalgesia
is similar and, therefore, differentiating between the two entities is a clinical
challenge. Despite similar presentation, there are a few differences between
opioid tolerance and opioid-induced hyperalgesia. In both the situations, the
previously used dose of opioid does not produce the desired effect but the pain
of OIH is diffuse and ill-defined. The area of distribution and intensity of pain
usually being greater than that in pre-existing pain.1 It may also mimic opioid
withdrawal pain7 and it definitely worsens with an increased dose of opioid.1
Opioid-induced Hyperalgesia 175
On the other hand, character as well as the distribution of pain do not change
in opioid tolerance. Just the previous dose no longer has the same effect; and
increasing the dose produces the desired effect with pain amelioration.3
EXPERIMENTAL EVIDENCE FOR EXISTENCE OF OIH

A progressive decrease in pain threshold was reported in mice following
intrathecal administration of morphine.7 Similar observations were made with
repeated doses of fentanyl8 and heroin.9 A mechanical allodynia and/or thermal
hyperalgesia has been reported after both acute and chronic administration of
opioids in rats.8 Hyperalgesia following heroin administration, lasting for as long
as 4 weeks has also been reported.9 Remifentanil when used for post-surgical
pain produced pro-nociceptive effects in mice. When a second surgery was
performed with remifentanil as anesthetic, the hyperalgesia was noted to have
increased.10 Both systemic and intrathecal morphine produced hyperalgesia
in rats11 and a long-lasting hyperalgesia was induced by fentanyl.12 Opioid
induced enhanced incisional pain has been reported in rats and after four
days of escalating-dose morphine administration, mice displayed allodynia
to mechanical stimuli.13 It was also noted that tolerance and hyperalgesia can
co-exist. Thermal hyperalgesia associated with morphine tolerance12 and both
tolerance and hyperalgesia with heroin have been reported. 14 Rats anesthetized
with sevoflurane and remifentanil displayed both tolerance and hyperalgesia and
naloxone reversed the hyperalgesia but not tolerance.15
CLINICAL EVIDENCE FOR OIH

There are many human volunteer studies as well as clinical studies that
substantiate the occurrence of opioid-induced hyperalgesia. Hyperalgesia
induced by opioids was recognized and reported in opioid addicts by Crompton P
and Doverty M.5,6 Guinard et al reported enhanced postoperative pain despite
increased postoperative remifentanil use in patients who received high doses of
intraoperative remifentanil.16 Hyperalgesia has been reported after a month long
treatment with oral morphine17 and following the use of opiates for management
of chronic pain.18
Opioid-induced hyperalgesia is not limited to chronic use of opioids. It has
also been reported after short-term infusion of remifentanil.19 Wolfgang Koppert
induced pain in 13 human volunteers using transcutaneous nerve stimulation
and assessed pain ratings as well as area of hyperalgesia before, during and after
remifentanil infusion and concluded that remifentanil reduces pain ratings
during infusion but increases pain ratings and also the area of hyperalgesia, after
the infusion is discontinued.20
An evidence based review provided emphatic evidence that normal human
volunteers experienced hyperalgesia following administration of acute morphine
infusions. The authors suggested that the metabolite morphine 3-glucuronide
may be implicated in the development of opioid induced hyperalgesia.21
Bannister et al in a review opined that the entity of opioid induced hyperalgesia
exists and that it is confounded by the specific opioid, the route of administration
and the pain modality tested.22 The first systematic review and meta-analysis of
postoperative patients concluded that the intraoperative use of high doses of
remifentanil definitely cause OIH for first 24 hours after surgery, the effect being
most prominent at 1 hour after surgery.23
PATHOGENESIS OF OIH
Though still not completely understood, the genesis of OIH is probably best
explained by the ‘opponent process theory’. As per this theory, the drug brings
about a desired effect, anti-nociception in the central nervous system. This
establishes itself in a short time and is predictable with repeated doses. At the
same time, a chronic or repeated use of the drug stimulates certain endogenous
compensatory reactions within the central nervous system that have an opposite
effect, i.e. pro-nociception. Thus, once the two opposing processes are active, the
degree of pain perception or pain relief will depend on the final outcome of the
interplay between the two opposing activities within the system.9
The pro-nociceptive effect is typically a late response and once established,
leads to perception of intensified pain or hyperalgesia, whenever the drug is
administered. Many mechanisms and pathways leading to the development of
the pro-nociceptive effect have been suggested. These are:
Desensitization of the Receptors

It is known that opioids exert their anti-nociceptive effect by binding to four
types of receptors (µ, d, k and ORL-1). They act via guanine nucleotide binding
protein (G–protein). Once bound to the G–protein, opioids cause K+ efflux and
subsequent closure of voltage-gated Ca++ channels, which is responsible for
hyperpolarization, decreased neuronal excitatory activity and resultant anti-
nociception. While the above process is going on, other enzymes are involved
in phosphorylation of the receptors. These are protein kinase C (PKC), b
adrenergic receptor kinase-2 and b arrestin–2. PKC is the main enzyme involved
in this process. Phosphorylation of the receptors causes desensitization. This
desensitization process has been observed to be homologous. Thus with the use
of selective µ agonists, selectively µ receptor desensitization would take place.24
With desensitization of receptors, the ionic changes are reversed and anti-
nociceptive effect decreases. The excitatory neuronal activity thus gets stimulated
and the pro-nociceptive effect becomes dominant over the anti-nociceptive
effect. Hence, there is perception of intensified pain instead of pain relief on
repeated or chronic use of opioids. The receptors exist as homodimers (µ/µ, d/d,
k/k, etc.) as well as heterodimers (µ/d, d/k, d/b2, etc.) and many subtypes are
known. That explains why the use of say selective d agonist opioid can prevent
desensitization of say µ receptors agonist morphine.25 It is also possible that the
desensitization process may be mediated via NMDA receptors as well.
Activation of Adenylate Cyclase Activity

Once the agonist binds to the receptor, the enzyme adenylate cyclase gets-
deactivated. The resultant decrease in intracellular cyclic adenosine mono
phosphate (cAMP) is responsible for hyperpolarization, decreased neuronal
activity and anti-nociception. A prolonged and sustained application of agonists
however upregulates adenylate cyclase activity via Gs proteins, resulting
in elevated levels of cAMP. This, in turn, facilitates presynaptic release of
excitatory neurotransmitters. This is followed by increased neuronal excitation

and resultant pronociception.26
Activation of NMDA Receptors

Once the opioids bind to the N-methyl-D-aspartate (NMDA) receptors, the
complex formed opens the Ca++ channels and allows influx of calcium ions. This,
in turn, increases protein kinase C with resultant phosphorylation of µ receptor-
opioid complex, thereby desensitizing the receptors. At the same time there is also
activation of NO synthetase enzyme. This leads to an increase in NO levels. NO
decreases the anti-nociceptive potency of µ receptors. Therefore, the opioids now
act synergistically with excitatory neurotransmitters enhancing pain perception,
by not only desensitizing the receptors, but also decreasing their anti-nociceptive
potency.27
Antiopioid Protein Release

A chronic exposure to opioids causes induction of antiopioid proteins. Some
of these have been identified, such as cholecystokinin (CCK), neuropeptide
PF, nociceptin and dynorphin A. These proteins bind to NMDA receptors and
cause a pro-nociceptive effect.28 This is further supported by the observation that
blocking these proteins results in potentiation of opioid analgesia.29
Facilitation of Descending Pain Pathways

It has been found that when µ receptors are continuously exposed to agonists,
there is promotion of synaptic transmission in the dorsal horn neurons.29,30 This
is brought about by stimulation of ‘on cells’ in rostroventral medulla (RVM). ‘On
cells’ are responsible for enhanced synaptic transmission of signals. This effect
is further potentiated by cholecystokinin and nociceptin-induced inhibition
of ‘off cells’. ‘Off cells’ normally retard transmission of neuronal signals.31 This
observation is further supported by the reports that application of CCK/CCK B
antagonists potentiate morphine analgesia.32
5HT3–Induced Upregulation of Genes Responsible for Nociception

Chronic or repeated morphine administration has been linked to activation of
5HT3 receptors in the dorsal horn. This leads to upregulation of genes responsible
for abnormal build-up of inflammatory mediators like substance P and calcitonin
gene-related peptide (CGRP) in the dorsal nerve ganglion. Both are proteins with
pro-nociceptive effects and enhance pain perception.33 5HT3 receptor blockade
with systemic and intrathecal ondansetron, a 5HT3 antagonist, reverses this effect
and decreases or prevents OIH.34
Inhibition of P Glycoprotein System

Normally P-glycoprotein system is involved in secreting or removing morphine
and its metabolites from the central compartment. Inhibition of this system leads
to build up of morphine and its metabolites in the brain and cerebrospinal fluid.35
This would ensure a continued receptor sensitization and de-sensitization
process and thus promotion of pro-nociception.
Opioid-induced Neuronal Apoptosis

Prolonged exposure to morphine causes neurotoxicity via NMDA receptors.24,26
This ultimately leads to neuronal cell death which is linked to both development
of tolerance and opioid-induced hyperalgesia.
Abnormal Catechol-O-Methyl Transferase (COMT) Activity

This enzyme is responsible for the breakdown of dopamine and noradrenaline.
Genetic makeup with substitution of the amino acids leads to varying degrees
of dopamine and noradrenaline breakdown, and subsequent availability at the
neuronal synapse. This could be responsible for varying degrees of neuronal
recruitment and decreased endogenous pain inhibition. Such a phenomenon
thus could be responsible for pain modulation and opioid-induced hyperalgesia
too.28,36
The neurobiological processes involved in the development of OIH are very
complex and not well understood till date. It is very likely that more than one
pathway stated above may be collectively contributing to the genesis of OIH.
Also the processes involved in development of tolerance and OIH may be similar
or common till some stage of the development of the two entities. Though the
processes involved in OIH following acute and chronic opioid administration
seem to be similar, further studies and time will reveal if some unexplored
pathways separate the pathogenesis in the two situations.
SITES OF OIH DEVELOPMENT

Just as anti-nociceptive processes take place at spinal and supraspinal levels,
pro-nociception also occurs at both sites. This is substantiated by laboratory data.
Daily intrathecal bolus administration of morphine in rat led to development of
opioid-induced hyperalgesia. Intrathecal morphine infusions caused less opioid-
induced hyperalgesia than intrathecal boluses with intermittent withdrawal.
Blockade of intrathecal NMDA receptors decreased or reversed this effect.37
Supraspinal origin of opioid-induced hyperalgesia is obvious, following
reports that injection of local anaesthetic into RVM or lesion of descending
fibers from RVM reverses opioid-induced hyperalgesia and also tolerance. CCK
released in RVM probably activates descending influences thereby modulating
pain perception. 5,29
REVERSING THE EFFECTS OF OIH

Since a pathological activation of NMDA receptors and glutaminergic system
is implicated in the development of opioid-induced hyperalgesia, targeting
this system is likely to overcome or attenuate the process of OIH. Some known
NMDA receptor antagonists have been effectively used clinically to overcome the
problem.
• Ketamine, a phencyclidine derivative exerts its anesthetic effects through
NMDA receptor binding. Besides anesthetic effects its NMDA receptor
binding has been found to be beneficial in management of many chronic-
neuropathic pains.38 In human volunteers, S-ketamine abolished remifentanil
induced hyperalgesia induced by intradermal electrical stimulation and also
remifentanil induced postoperative hyperalgesia.25,39
• Methadone is a weak NMDA receptor antagonist and offers many advantages

as it exhibits incomplete cross-tolerance with opioid-receptors.40 It has been
effectively used for opioid rotation to overcome or significantly reduce OIH.41,42
However in one report, it has been also implicated in worsening OIH.43
• Dextromethorphan is also an NMDA receptor antagonist. Although its direct
role in offsetting OIH has not been established, indirect evidence suggests
that it may have a role to play in reducing tolerance and OIH; since a (1:1)
combination of dextromethorphan and morphine has been found to be a
better analgesic than morphine alone, for non-malignant chronic painful
conditions.44
• Experimental evidence points toward a possible role of propofol in modulating
OIH via supraspinal g-aminobutyric acid (GABA) receptors.45
• COX-2 inhibitors have been shown to antagonize NMDA receptors and reduce
tolerance to opioids in animal experiments.46 In humans, COX-2 inhibitors are
also believed to decrease prostaglandin secretion in spinal cord and reduce
the formation of neuroexcitatory amino acid glutamate, thereby modulating
OIH.47
• a2-receptor agonists have a positive role in modulating OIH as shown in both
animal and human studies. A single dose of clonidine effectively attenuated
the thermal hypersensitivity for 24–30 hours in rats.48 Further confirmation
of its role was evidenced by the fact that co-administration of d2 antagonist,
idazoxan, prevented this effect.49
TREATMENT STRATEGIES
Opioid-induced hyperalgesia presents a clinical challenge to the treating
pain physician, since an increase in pain not only debilitates but also leads
to behavioral problems. A demand for an increase in pain relief may be
attributed to anxiety, fear of pain and isolation. While the sufferer is impatient
for immediate relief, diagnosis and management requires both patience and
time.
Many strategies to treat OIH are available; and with trial and exclusion, the
most suitable solution can be found. These include:
• In case of suspected opioid tolerance, the dose of opioid can be increased
and should result in pain amelioration. Even if pain relief is not established,
there should be no further aggravation of pain. Gradual increase in dose
will re-establish the pain relief, but care is needed not to exceed toxic limits.
• Withdraw or eliminate the opioid and evaluate for OIH. However, with this
strategy opioid withdrawal symptoms may emerge and need to be managed.
• “Opioid rotation” involves substitution the offending opioid with another
opioid that has µ antagonist and k agonist effect. Kappa receptors till
date have not been definitely implicated in the development of OIH and
thus k agonist will exhibit their analgesic effect; and since µ receptors are
implicated in development of OIH, µ antagonists will delay or even inhibit
OIH.
Nalbuphine and buprenorphine have been effectively used in
overcoming OIH.50 Buprenorphine is a partial agonist and antagonist.
It prevents the k agonist effect of dynorphin which increases with opioid
use and has been implicated in development of OIH, and buprenorphine

has also exhibited an enhanced ability to reverse the hyperalgesia
experimentally induced in volunteers, as compared to fentanyl.51
Methadone is a racemic mixture. Although a pure µ-receptor agonist,
its d-isomer is an NMDA receptor antagonist. Cross-tolerance with other
opioids is known but incomplete. Patients suspected to have OIH have been
successfully treated with reducing the dose of opioid with concomitant
addition of a small dose of methadone.52
Morphine has also been successfully rotated with hydromorphone and
oxycodone, and even transdermal fentanyl.53
• Co-administration of NMDA antagonists like ketamine has been effectively
used to reduce morphine requirements postoperatively.54
• Co-administration of COX-2 inhibitors and paracetamol have been found to
have a beneficial effect when co-administered with opioids, and is credited
with the potential for preventing OIH.55
• Co-administration of a2 agonist clonidine has been found to potentiate the
opioid analgesia.56 It has also been reported to delay or decrease OIH and
control opioid withdrawal symptoms.57
• Use of naloxone in ultra-low doses have been reported to reverse
remifentanil-induced OIH in rats. Naloxone is postulated to act by blocking
the G-protein coupling with µ receptors and also by attenuating NMDA
regulated spinal transmission, both actions favoring reversal of OIH.58
Clinical trials are needed to establish the efficacy of naloxone in reversing
OIH in humans.
CONCLUSION
Despite a lot of available literature, the entity of OIH remains an enigma. More
studies are required to fully understand the genesis of the entity OIH, and more
clinical trials are needed to establish rational use and the superiority of one
treatment strategy over the other in reversing and minimizing the effect of OIH
and even preventing it.
KEY POINTS
• O pioid-induced hyperalgesia is a definite entity and closely mimics opioid tolerance.
• It develops mainly as a result of desensitization of the µ receptors. Activation of adenylate
cyclase activity and NMDA receptors also contribute towards pro-nociception.
• Other pathways suggested include 5HT3 induced upregulation of genes responsible
for build-up of inflammatory mediators, abnormal catechol–O–methyl transferase
activity, and neuronal apoptosis; which facilitates transmission through descending
pain pathways.
• Opioid-induced hyperalgesia can be effectively countered with ‘opioid rotation’,
especially with the use of agonist and partial antagonists such as methadone and
buprenorphine; concomitant use of NMDA receptor antagonist such as ketamine, α2
agonist clonidine, propofol and COX-2 inhibitors.
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CHAPTER 16
Anesthetic Management of
Faciomaxillary Trauma
Anil Kumar Jain
INTRODUCTION
Anesthesiologist manages maxillofacial trauma victims in emergency area, in the
operation theater as emergent or elective case for correction of deformities. In all
situations meticulous airway management is central to the safety of patient. Some
of these patients succumb at the accident site due to suffocation and asphyxia
produced by acute airway obstruction. Of those who survive acute onslaught,
a significant percentage is at risk of airway compromise, hence require diligent
care, observation and expert airway handling. Besides bleeding which is not a
major problem in these cases, spinal and cranial injuries are other concerns.
INCIDENCE AND ETIOLOGY OF MAXILLOFACIAL TRAUMA

Broadly, assaults, falls, sports injuries, road-traffic accidents (RTA), industrial
accidents and war injuries are responsible for most maxillofacial injuries
worldwide, but cause differ according to world location (Table 16.1).1 In recent
time, the etiology of oral and maxillofacial injuries and treatments has undergone
tremendous change. Patterns of injury have changed and they continue to change.
Through legislation, improved health, safety awareness, and safety-design there
has been a reduction in the severe facial injuries previously associated with RTA
in metro cities. However, terrorism, interpersonal violence, and the use of drugs
and alcohol has become prominent offender. Aging population may lead to a
higher number of facial fractures in the elderly caused by falls. Moreover, modern
society is seeing an increase in war and terror injuries.2,3
Table 16.1 Etiology of fractures sustained in patients through the world (percentage of
total number of facial fractures)
Africa Australia New United United India
Zealand Kingdom States
Assault 57.2 51.3 32.4 52 48.2 24.6
RTA 105.1 18.8 29.6 16 43 40.3
Sport 10.5 16.3 19.6 19 3.8 4
Falls 19.4 9.7 9.2 11 3.6 24
Gunshot — 0.7 — — — —
Industrial 4.2 1.5 — 2 0.4 1.3
Other — 1.7 9.2 — — 1.2
Anesthetic Management of Faciomaxillary Trauma 185
ANATOMY
Knowledge of the maxillofacial anatomy is essential for the proper management
of maxillofacial trauma. The human skull has two major parts: the calvaria, which
encloses and protects the brain, and the facial skeleton with mandible. The facial
skeleton is also subdivided into the following three parts:
1. The upper face: Fronto-zygomatic processes and the frontal bone.
2. Mid-face: Nasal bones, orbits, ethmoid bone, zygomatic bones and maxilla.
3. Lower face: Mandible.
The zygomatic bones together with frontal and temporal bones form a
series of arches and buttresses to protect the intracranial contents. The muscles
involved in mastication (temporalis, masseter and pterygoids) are attached
to the mandible to fully open the mouth and produce a hinge-like and gliding
movement at the temporomandibular joint (TMJ).4
CLINICAL PRESENTATION
Both bones and soft tissues are involved in faciomaxillary trauma. Bony injuries
can be classified according to the face portion involved.
Upper Face Fractures

Fractures involving the sinuses and frontal bone are common. Presentation
includes disruption of the supraorbital rims and paresthesia of the supratrochlear
and supraorbital nerves.
Mid-face Fractures
Fracture involving zygomatic arch, nasal bones, orbital floor, nasoethmoid and
maxilla. The mid facial fractures are named after Rene LeFort, three patterns of
mid-face fractures were identified (Figs 16.1A to C).4,5
Lower Face Fractures

Involve fractures of the mandible. Condylar fracture presents as tenderness
anterior to the external auditory meatus. Mandibular body fracture present
as painful jaw movement and malocclusion of the teeth. Bilateral mandibular
A B C
Figs 16.1A to C: LeFort fractures Type I-III
fracture can present as an anterior open bite or posterior inferior an open hanging
mouth. At times displacement of the fractured mandibular segment can cause
airway obstruction.
Pan-facial Fractures
This includes fractures of the upper, mid and lower face. Physical findings depend
on the combination of fractures sustained.
LeFort I: This is a dentoalveolar horizontal fracture that separates the maxillary
alveolus from the mid-face. It presents as facial edema and mobility of the hard
palate, maxillary alveolus and teeth.
LeFort II: This is a pyramidal or triangular fracture that separates maxilla from
the zygoma. Clinical presentation includes facial edema, subconjunctival
hemorrhage, telecanthus, mobility of the maxilla at the nasofrontal suture,
epistaxis and possible cerebrospinal fluid (CSF) rhinorrhea.
LeFort III: This is a complete dislocation of the facial skeleton from the cranial
skeleton running parallel to the skull base. Characteristic findings of LeFort III
include massive edema with facial rounding or elongation and flattening and
movement of all facial bones in relation to the cranial base with manipulation
of the teeth and hard palate. Epistaxis and CSF rhinorrhea may also be present.
AIRWAY MANAGEMENT
Airway Assessment
Airway is most prominent issue is these patients, its assessment obviously is
necessary to avoid accidents and complications. Patients with impending or
existing airway compromise require immediate assessment and management.
Because of urgency, only clinical assessment is possible in some patients.
Clinically, the level of consciousness, anxiety, ability to phonate, stridor, use of
accessory muscle of respiration and tracheal deviation are some of the features
of note, which suggest need for early airway intubation. In these patients danger
of airway compromise and difficulties with oxygenation forces one to perform
rapid airway evaluation according to the advanced trauma life support (ATLS)
protocol.6,7 Benumof airway assessment steps could be undertaken. There are
several methods of predicting and managing patients with difficult airway.7,8 The
airway difficulties are often unforeseen, as methods available have poor sensitivity
and predictive values; nearly half of all difficult laryngoscopies are unpredicted.9
Pharyngeal hemorrhage and bilateral mandibular fractures may lead to
upper airway obstruction, particularly in a supine patient (Fig. 16.2). Therefore, a
patient found in the sitting or prone position because of airway compromise is best
left in that position until the moment of anesthetic induction and intubation.10
An oral or nasopharyngeal airway may be required to maintain a patent
airway until endotracheal intubation can be attempted in a controlled and
equipped area of the hospital.11
Other Related Assessments

Cervical spine and head injury: If injury to the cervical spine and head goes
undiagnosed or untreated consequences are catastrophic. In all patients with
Fig. 16.2: Maxillomandibular fracture
central neurologic deficit, severe polytrauma and also significant blunt injury
above clavicle, cervical spinal injuries should be assumed and ruled out. These
patients should receive spine immobilization and where appropriate, standard
treatment for the prevention of secondary brain-injury.
Full stomach: Trauma patients should as a rule be considered nonfasted. Airway
techniques and the induction of anesthesia need to be modified to allow for and
guard against airway soiling.
Oxygenation status: Oxygenation is of primary concern and should not be
compromised during formal efforts to secure an airway. Patient’s oxygen
requirement clearly needs to be met, and titrated to prevent hypoxia. Clinical
observation, and monitoring (oximetry/arterial blood gas) should be used to
ensure oxygenation. Variable performance devices, such as, nasal cannulae or
Hudson face masks should be used for adequate oxygenation.
BASIC AIRWAY MANAGEMENT TECHNIQUES

Flow chart 16.1 depicts the flow diagram for assessment and management of
the airway in a trauma patient. If airway is compromised, arterial hypoxemia
will ensue, even with highest fraction of inspired oxygen. Reduced level of
consciousness is a common cause of obstructed airway. The use of a simple bag
and mask may provide enough positive airway pressure to open an airway. In
some situations simple bag-mask airway techniques may not be tolerated and
may even be futile because the airway is disrupted. The positive airway pressure
may insufflate the stomach and increase the risk of regurgitation and aspiration.
Basic airway maneuvers may help to open the airway—for example, chin-lift
and head-tilt provided cervical spine trauma is ruled out. In addition, there
are basic airway adjuncts which may greatly assist in the airway management.
Oropharyngeal and nasopharyngeal airways can serve to secure an unobstructed
channel.
Flow chart 16.1: Airway management
Patient positioning is of great importance. Correct alignment of a patient’s

airway by proper position can transform disastrous “cannot ventilate and cannot
intubate” situations into more easily managed ones. Patients may be raised to
elevated, near-sitting positions, such that the external auditory meatus and the
sterna notch are horizontally aligned.11 It has been shown that preoxygenating in
a 25° elevated position is more effective.12,13 Awake and co-operative patients may
not need the airway to be formally supported.
Standard Intubation
Inability to maintain oxygenation due to obstructed airway demands immediate
escalation of treatment. Moreover, in situations of progressive loss of the airway,
such as with increasing edema or hematoma, it may be necessary to secure
the patient’s airway early. Oxygenation should always be ensured at all times.
Advanced methods of airway management should not be undertaken at the
expense of patient’s oxygenation.
For airway protection, first choice often is oral endotracheal intubation. As
a definitive airway, this secured, cuffed, endotracheal tube not only protects the
airway but also facilitates ventilation and oxygenation. However, a nasotracheal
tube may be preferred to an oral tube as it may offer a better field of vision from
a maxillofacial surgeon’s perspective. Unfortunately, nasal intubation can have
significant failure rates. For instance, a case series found 13.2% failure rate of
nasotracheal intubation. Basal skull fractures and, in some instances, midfacial
fractures rule it out. Moreover, flexion or rotation of the neck is often necessary
for its success. Obviously this will be contraindicated in patients with unclear
cervical spines. Nasal intubation can further traumatize the airway, and epistaxis
increases the risk of aspiration and failure to secure the airway.
Correct patients positioning, often overlooked in emergency situations,
is essential. It may require the removal of spinal boards and collar protection
devices. Extra-tracheal pressure, such as the backwards upwards rightwards
pressure (BURP), may help. There is a vast and diverse array of laryngoscopes
and blade attachments, and it is beyond the scope of this chapter to cover them
all in detail.
Intubating Stylets and Airway Adjuncts

Introducers, preformed or otherwise, are used to aid tracheal intubation. These
devices are invaluable, gum-elastic bougie often being the first recourse when
laryngeal visualization is less than straightforward. These devices needs care in
their handling, as they may worsen airway trauma.14 To oxygenate the patient as
often as required during intubation led to the development of the aintree intubation
catheter (AIC) (Cook Medical, UK) and the ventilating bougie (Timesco, UK). The
AIC can be inserted into the trachea over a fiberoptic laryngoscope. It can also
be positioned by passing it through a supraglottic airway. Despite its relatively
narrow diameter, it has a 15 mm connector, and can be used to oxygenate and
ventilate a patient as an airway device.
Rescue Techniques
Due to many reasons anesthesiologists may struggle to secure patient’s airway.
Difficult anatomy, distorted anatomy, swollen airway and inability to prepare
appropriately can make visualization of the vocal cords impossible. When
standard intubation attempts with a laryngoscope fail, oxygenation should
be maintained. Failed intubation can have serious clinical sequel, but failure
to oxygenate is always calamitous. Anesthesiologist is confronted with many
challenges because of complex and acute presentation of maxillofacial trauma
and many options of treatment and equipments. It should be noted that a lack
of familiarity with the technique actually used for intubation, increases the risk
of complications. It is important therefore that clinicians ensure they are familiar
with the techniques they choose, and that they have contingency plans.15
One of the common errors when faced with difficult airway management
is the repeated attempt at standard intubation before attempting another
method. This has been recognized as one of the surest predictors of bad patient
outcome, even when airway is subsequently secured. When it is not possible to
secure and protect an airway using standard methods, it may be necessary to
use airway devices that do not formally protect the airway but at least facilitate
ventilation and therefore oxygenation. Such devices may also be subsequently
helpful in securing a definitive airway. Such equipments are broadly classified as
supraglottic or infraglottic.
Supraglottic Devices
Laryngeal mask airway: Laryngeal mask airway (LMA) has been incorporated
into advance difficult airway algorithms (Fig. 16.3).16-20 It may reduce the risk
of aspiration, when compared with bag mask ventilation. However, insertion
may stimulate a risk of laryngo/broncho spasm or regurgitation. Some evidence
suggests that it can produce significant movement of the cervical spine, which may
be relevant in patients of the maxillofacial trauma. Second-generation version the
proseal laryngeal mask airway (PLMA), incorporates separate gastric channels
into their design. This allows the passage of orogastric tubes to decompress the
stomach. Such devices reduce the risk of aspiration by permitting regurgitant
material to bypass the supraglottic area.
Laryngeal mask airways (LMAs) can also be used to facilitate intubation.
The intubating LMA (ILMA) has been used in emergency situations not only to
maintain airway but also to guide blind intubation.21 Moreover, in this regard, the
ILMA has proved successful in patients with difficult airways22 and the rates of
successful intubation compare favorably with those with fiberscopic intubation
techniques. They also have a lower incidence of adverse events, such as oxygen
desaturation.23 There are case examples of the ILMAs use in patients suffering
from maxillofacial trauma where traditional face-mask ventilation laryngoscopy,
and fiberoptic intubation were deemed difficult and inappropriate.23
Advances have also been made in sight-guided placement of the endotracheal
tube by attaching fiberoptic bundles to the distal ends of the LMA’s airway tube.
An example of this type is the LMA CTrach, which is a modification of the ILMA.
Other double–lumen laryngeal devices: First appeared in the late 1960s as an
alternative to endotracheal intubation during emergency,24 double-lumen
devices have been used to access the airway during CPR25,26 and trauma.27 The
Combitube is perhaps the best-known DLD, other examples are King-LT and the
Laryngeal Tube LTS II airway device from VBM Medizintechnik.
Direct and Indirect—Vision Devices

Semi-rigid fiberoptic stylets: These are used in situations of unanticipated difficult
intubations and to monitor routine intubation. These instruments incorporate
fiberoptic bundles into a semi-rigid stylet and can be used alone but have a higher
success rate when used with standard direct laryngoscopy.28 Shikani optical and
Levitan stylet are example of stylets.
Rigid fiberoptic stylets: Bonfils intubation fiberscope can be used by a midsagittal
approach. It can also be deployed via a retro-molar approach. With this approach,
the scope is passed posterior to the molar teeth and into the posterior pharynx,
thereby visualizing the glottis. It can be useful in those with limited mouth
opening. Unfortunately, because of its rigid nature, it cannot be used for nasal
intubation. The Bonfils fiberscope was used by ENT surgeons for decades.
Fiberoptic laryngoscopes: The Bullard laryngoscope is an example of an indirect
fiberoptic laryngoscope. It has several advantageous features. At the distal end
of its rigid, anatomically shaped blade, it has a bundle for light-transmission and
one for image-transmission, thereby providing good quality images of the larynx.
It has a working channel for the suctioning of secretions and the administration
of, for instance, oxygen or local anesthetics.29
Video-laryngoscopes: They are form of indirect laryngoscope. Examples are

glidescope, McGrath, storz and Pentax new Airway scope.
Prism devices: The airtraq optical laryngoscope can be useful, where a direct
laryngoscope has failed.
Traditional flexible fiberscope devices: Many authorities regard awake fiberoptic
intubation as the gold standard in securing the difficult airway. This is reflected
in the American Society of Anesthesiologists (ASA) Practice Guidelines, which
state that an awake intubation is the primary method for securing a suspected
difficult airway.30 It must be stressed once again that the patient’s most important
need is adequate oxygenation. This must take precedence over even a formally
secured airway. Fiberoptic intubation may therefore be considered a second-
line technique, to be used when oxygenation has already been ensured.16-20
Destruction of normal anatomy and impairment of vision from blood and
debris may make this technique practically difficult. In the maxillofacial trauma
situation, even with a cooperative patient who is not in need of immediate
airway protection, this technique may fail. Often the nasal approach is favored,
which may potentially carry similar risks to nasogastric tube insertion. Also,
the inflammation and trauma sustained by a maxillofacial injured patient may
prevent topically applied local anesthetic from taking effect.
Infra-Glottic Airway Devices: Cricothyroidotomy

In maxillofacial trauma, significant upper-airway distortion may occur, which
make it impossible to access the larynx from above. The potentially disastrous
consequences of prolonged hypoxia must be avoided, and early consideration
be given to direct tracheal access via surgical or percutaneous tracheostomy or
needle or surgical cricothyroidotomy. Needle and surgical cricothyroidotomy
techniques are widely recommended.16-20
Cannula technique: Emergency cannula cricothyroidotomy and jet-ventilation
may be performed. This involves jet-ventilation through a cannula inserted
into the trachea via the cricothyroid membrane.31 This may provide sufficient
oxygenation for a period of time and is only a temporizing measure.
Surgical technique: If supra glottic techniques are not capable of oxygenating
the patient, formal surgical cricothyroidotomy, according to the Difficult Airway
Society’s guidelines, is the preferred emergency surgical approach to the airway
and should be performed next.31 Two main approaches to cricothyroidotomy
are the ‘open’ and the ‘percutaneous’. In the percutaneous approach, a typical
Seldinger technique is used. Following needle aspiration of air through the
cricothyroid membrane, a guidewire is inserted. After tract dilation, this guidewire
subsequently allows the passage of either an endotracheal or a tracheostomy
tube.
Open surgical cricothyroidotomy is performed by making an incision through
the cricothyroid membrane.
Retrograde Intubation
It may be a lengthier procedure than other methods of securing airway but
provide both ventilation and airway protection. On its own, this technique does
not offer means of oxygenation until it is completed, which indicates that it may
be unsuitable in some situations. However, the laryngeal inlet does not have to be
visualized, which may be useful in some maxillofacial trauma patients.32
FACTORS AFFECTING EMERGENCY AIRWAY MANAGEMENT

IN MAXILLOFACIAL TRAUMA
• Distorted anatomy: The maxillofacial trauma may be associated with both
difficult mask ventilation and difficult intubation. Mechanical trauma,
bleeding and edema usually disrupt the normal anatomy which makes mask
ventilation and intubation difficult.33-34
• C-spine injury: Cervical spine injury in patients with maxillofacial trauma has
been reported to be associated in up to 6% of cases.35-37 However, any patient
with maxillofacial trauma should be considered to have associated C-spine
injury until proven otherwise.
• Full stomach: Like any trauma patient, these patients should always be
considered to have a ‘full stomach’.
• Laryngotracheal injury: Laryngeal injuries are rare but when present may
lead to life threatening airway obstruction.38 Nearly 96% of patients with
laryngotracheal trauma have associated maxillofacial injuries.39
• Emergency situation: Emergency airway management poses an additional
difficulty as both decision making and the time to accomplish the task are
short and the patient’s condition may deteriorate quickly.
• Availability of experienced personnel: Several studies have shown that proper
assessment, timely decision making and execution of treatment priorities
reduce the complication rate particularly when trained and experienced
personnel are available. However, in most of the emergency situations, the
‘inverse care law’ is applied, i.e. the care of these critical patients are in the
hands of personnels who are not so expert in managing these cases.40,41
MANAGEMENT OF HEMORRHAGE
In maxillofacial trauma bleeding is usually not a major issue. Superficial bleeding
may occur from middle third of face or base of skull and required expert care
and management. Tongue laceration is sometime difficult to control and may
require arterial embolization to control hemorrhage, when common modalities
of treatment are ineffective.
OTHER CARE
Infection prevention by use of appropriate antibiotic and primary wound care is
mandatory. Broad spectrum antibiotic, also covering anerobes is recommended.
Soft tissue injuries especially lacerations should be thoroughly cleaned and
sutured. Wound should be watched for edema and swelling.
ELECTIVE OR LATE MANAGEMENT

After initial stabilization, when edema has decreased definitive surgery, when
required should be planned.42 Besides head and neck, systemic examination,
airway evaluation is very important.
A review of preoperative radiological imaging to assess airway and extent

of injury may helps us in formulation of an appropriate management plan
(Fig. 16.3). It also depicts associated head and spine injury.
ANESTHESIA MANAGEMENT
Main anesthetic considerations are airway management, oxygenation and
selection of an appropriate anesthetic agents to ensure early recovery. Airway
related complications could occur any time in the perioperative period.12 One
can take help of Benumof’s airway assessment eleven steps for its evaluation.43
Difficult airway cart, extra helping hands and appropriate monitoring
should be available. The anesthesia technique should be chosen based on a
Fig. 16.3: CT scan of faciomaxillary trauma

patient’s injuries, airway and anesthesiologists experience. If difficult intubation

is expected, muscle relaxants should only be used after securing the airway.
Inhalational induction of anesthesia is performed by most and ability to mask
ventilation evaluated. If anesthesiologist is losing airway patency during
inhalation induction of anaesthesia, it is discontinued and awake methods of
securing airway can be utilized.
ASA difficult airway algorithm, which institutionalized the need for airway
evaluation, awake intubation techniques, and the use of back-up rescue
modalities such as laryngeal mask airway (LMA), esophageal-tracheal-combitube
(Combitube), and transtracheal jet ventilation (TTJV) has produced significant
reduction in airway management claims over the past decade.12 It is therefore
logical that incorporation of the ASA difficult airway algorithm, with certain
modifications, can likewise improve safety during trauma airway management.
Orotracheal intubation and direct laryngoscopy is the preferred technique
with due care of cervical spine. The GlideScope (video laryngoscope) is designed
for the visualization of vocal cords with minimal manipulation and may be
helpful during a difficult intubation.44 Surgical airway is required, when it is not
possible to secure airway by other means and also when trauma is extensive and
require prolonged intubation.
Nasal intubation is preferred by some as it does not interfere in surgery. Nasal
route can cause many complication45-47 but other have found it safe even patient
with skull base fractures.48-49 When nasal intubation is not advisable, retromolar
intubation may be helpful in avoiding invasive procedures (tracheostomy, sub
mental intubation).17 After routine orotracheal intubation has been performed
with a slightly smaller endotracheal tube, the tube is pushed into the retromolar
space or missing tooth space and secured with stitches. The main advantage of
this technique is minimal interference in the surgical field and achievement of
proper intraoperative dental occlusion.
Classic sub mental technique of intubation involves standard orotracheal
intubation with an armoured tube, after which a small incision is made in the sub
mental region adjacent to the mandible. This is followed by creating a tunnel through
the muscular layers up to the oral mucosa using a blunt dissection technique. After
the access is made the tube is taken out through the tunnel and secured with sutures.
The sub mental intubation should be converted to an orotracheal intubation before
extubation. It is contraindicated when long term airway support is required.18 This
approach has been used successfully with few minor complications in maxillofacial
trauma. Infection of the wound, salivary fistula, mucocele and hypertrophic scar
are some of the relatively rare complications of the sub mental approach which can
be avoided by using a meticulous technique.38
Submandibular intubation is a modification of sub mental intubation where
the incision is made posteriorly in the submandibular area, avoiding injury to the
important salivary structures (sublingual and submandibular ducts and lingual
nerve). Anwer and co-workers have described the successful use of this approach
in maxillofacial surgical patients.19 Surgical airway is required when it is not
possible to secure the airway by other means.
Anesthesia is maintained with technique which ensure awake patient
with intact airway reflex. Modern volatile anesthetic agents like desflurane or
sevoflurane could achieve required objective or TIVA with propofol may be used.
Some may require delayed extubation in postsurgical care area and use of tube
exchanger may be helpful.
POSTOPERATIVE CARE
Difficult airway can pose problem of airway integrity during extubation.
Precautions similar to taken during intubation has to be in place. All airway
equipments including endotracheal tube exchanger should be there. Presence
of consciousness and reflexes are required for extubating trachea. Cuff leak test,
direct visualization of airway could rule-out airway edema. One should defer
extubation if there is any doubt about airway and extubate later in postoperative
care unit. All patients should be nursed in intensive care unit for observation
of vital signs and respiration. Patients with interdental wiring should have wire
cutter at bed side. Bleeding and oozing from trauma area could form hematoma
and impair airway. For pain control, multimodal analgesia, which include
paracetamol, nonsteroid anti-inflammatory drugs and opioid are used. These
patients have increased incidence of vomiting and nausea. Gastro prokinetics
and antiemetic helps in controlling PONV. Lastly throat pack removal should
never be forgotten.
CONCLUSION
Basic principles of trauma care should be followed in the management of
maxillofacial trauma patients. Prompt and thorough evaluation of the severity of
injury and successful airway management determines emergency department
survival. Direct laryngoscopy and orotracheal intubation is still considered the
technique of choice for securing an airway in the emergency department unless
contraindicated. Definitive surgical management should be scheduled later in an
elective manner. Difficult airway equipment including a fiberoptic bronchoscope
with the availability of alternative airway management techniques including
surgical airway and a clear back up plan are essential. The presence of an
experienced anesthesiologist with expertise in various types of airway equipment
and in managing maxillofacial trauma may improve patient care.
While intubation and the establishment of a definitive airway are important
aspects of airway management, ensuring adequate oxygenation to reduce the
incidence and impact of secondary injury is vital. Further harm to the patient
should not be caused by prolonged, incorrectly selected and failing airway-
management techniques. Advances, in recent years in particular, have increased
the range of equipment available to the anesthetists to help manage the difficult
airway. Each clinician must be familiar with the devices available in their own
departments. A lack of familiarity with equipment and technical options has
been associated with poorer clinical outcomes. Also associated with poorer
clinical outcome is an inability or lack of preparedness to escalate treatment
options. Clinicians must be both familiar with and confident in the routine use
of the difficult-airway equipment at their disposal and must be prepared to use it
without undue delay in an emergency. Should other more easily applied and less
invasive approaches fail, cricothyroidotomy remains the current fallback option.
KEY POINTS
• I ncreasing road traffic accidents, violence and terrorism result in frequent occurrence of
faciomaxillary and other trauma.
• Protocol based care, advanced trauma life support (ATLS) and difficult airway algorithm,
have led to reduction in mortality.
• Basic principles of trauma care as per ATLS protocol should be followed at every step.
• Airway management is central to their care, in emergency area and also in operation
suits.
• Detailed knowledge of maxillofacial and airway anatomy can help in understanding
the mechanism, diagnosing the extent and severity of injury and formulating a proper
airway management plan.
• Cervical trauma and also head injury should always be ruled out.
• Soft tissue swelling in airway could gradually compromise its integrity.
• Adequate airway expertise, experienced personnel and selection of optimum anes
thetic drug and techniques should ensure patient safety.
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15. Peterson GN, Domino KB, Caplan RA, Posner KL, Lee LA, Cheney FW. Management of
the difficult airway: a closed claims analysis. Anesthesiology. 2005;103(1):33-9.
16. Bracken CA. Base of skull fractures and intubation: archaic medicine or sound
rationale? J Trauma. 2001;50:365-6.
17. Malhotra N. Retromolar intubation—a simple alternative to submental intubation.
Anaesthesia. 2006;61(5):515-6.
18. Lima Jr SM, Asprino L, Moreira RW, et al. A retrospective analysis of submental
intubation in maxillofacial trauma patients. J Oral Maxillofac Surg. 2011;69(7):2001-5.
19. Anwer HM, Zeitoun IM, Shehata EA. Submandibular approach for tracheal intubation
in patients with panfacial fractures. Br J Anaesth. 2007;98(6):835-40.
20. Krohner RG. Anesthetic considerations and techniques for oral and maxillofacial
surgery. Int Anesthesiol Clin. 2003;41(3):67-89.
21. Baskett PJ, Parr MJ, Nolan JP. The intubating laryngeal mask. Results of a multicentre
trial with experience of 500 cases. Anaesthesia. 1998;53:1174-9.
22. Combes X, Le Roux B, Suen P, Dumerat M, Motamed C, Sauvat S, et al. Unanticipated
difficult airway in anesthetized patients: prospective validation of a management
algorithm. Anesthesiology. 2004;100(5):1146-50.
23. Komatsu R. The intubating laryngeal mask airway allows tracheal intubation when the
cervical spine is immobilized by a rigid collar. Br J Anaesth. 2004;93(5):655-9.
24. Don Michael TA, Lambert EH, Tehran A. Mouth-to-lung airway for cardiac
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26. Tanigawa K, Shigematsu A. Choice of airway devices for 12,020 cases of nontraumatic
cardiac arrest in Japan. Prehospital Emergency Care. 1998;2:96-100.
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28. Shaken AH. New “seeing” stylet-scope and method for the management of the difficult
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29. Turner CR, Block J, Shanks A, Morris M, Lodhia KR, Gujar SK. Motion of a
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38. Schaefer SD. The acute management of external laryngeal trauma. A 27-year
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associated with craniomaxillofacial trauma. J Oral Maxillofac Surg. 2006;64(2):203-14.
40. Boylan JF, Kavanagh BP. Emergency airway management: competence versus
expertise? Anesthesiology. 2008;109(6):945-7.
41. Kovacs G, Law JA, Ross J, Tallon J, MacQuarrie K, Petrie D, et al. Acute airway
management in the emergency department by non-anesthesiologists. Can J Anaesth.
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42. Raval CB, Rashiduddin M. Airway management in patients with maxillofacial trauma
a retrospective study of 177 cases. Saudi J Anaesth. 2011;5(1):9e14.
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Airway. Practice guidelines for management of the difficult airway: an updated report
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Difficult Airway. Anesthesiology. 2003;98(5):1269-77.
44. Robitaille A, Williams SR, Tremblay MH, Guilbert F, Thériault M, Drolet P. Cervical
spine motion during tracheal intubation with manual in-line stabilization: direct
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45. Hall CE, Shutt LE. Nasotracheal intubation for head and neck surgery. Anaesthesia.
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46. Marlow TJ, Goltra Jr DD, Schabel SI. Intracranial placement of a nasotracheal tube
after facial fracture: a rare complication. J Emerg Med. 1997;15(2):187-91.
47. Horellou MF, Mathe D, Feiss P. A hazard of naso-tracheal intubation. Anaesthesia.
1978;33(1):73-4.
48. Bähr W, Stoll P. Nasal intubation in the presence of frontobasal fractures: a retrospective
study. J Oral Maxillofac Surg. 1992;50(5):445-7.
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facial trauma. J Emerg Med. 1997;15(2):141-5.
CHAPTER 17
Critical Care in Head Injured Patients
LD Mishra, S Loha
INTRODUCTION
The incidence of traumatic brain injury (TBI) has risen to an alarming level in the
recent years, mainly involving the children and young adults. As reported in earlier
studies around 85% patients suffering from severe TBI remained disabled after
1 year and out of them only 15% returned to work at 5 year.1 Due to tremendous
increase in incidence of TBI in India in the past few years, it is often being referred,
to as a silent epidemic.2 Over 100,000 people die in India per year due to road
traffic accidents (RTA). Out of these approx 50–60% suffer with TBI.3 It has been
observed that implementation of protocols and guidelines for the management of
TBI is associated with substantially better outcomes.4
Primary injury occurs at the site of accident and therefore is not in control of
the clinician. Secondary injury is related to the subsequent neurological injury
that further augments the primary injury. Prevention and timely management of
different causes which can individually or in combination, worsen the condition
have a major impact on TBI outcome. Progression of this is predominantly
amenable to therapy, including the care offered in the critical/neurocritical care
units. Following is a list of main causative factors for secondary injury:
• Hypotension (SBP <90 or MAP <60 mm Hg) or hypertension (SBP >160 MAP
>110 mm Hg)
• Hypoxemia (PaO2 <60 mm Hg; SaO2 <90%)
• Hypocapnia (PaCO2 <35 mm Hg) or hypercapnia (PaCO2 >45 mm Hg)
• Anemia (Hb<10 g%, or Hct<0.30)
• Hyponatremia (<142 mEq/L)
• Hyper (> 180 mg/dL) or hypoglycemia (<80 mg/dL)
• Hypo-osmolality (<290 mOsm/kg H2O)
• Acid-base disorders (pH < 7.35 or > 7.45)
• Fever (> 37°C) or hypothermia (< 35.5°C).
MANAGEMENT OF TRAUMATIC BRAIN INJURY IN

INTENSIVE CARE UNIT
The management of TBI patients is primarily based on “Guidelines for the
Management of Severe Traumatic Brain Injury” which is reviewed by the Brain
Trauma Foundation (BTF) from time to time.1,2 The primary aim is to prevent and
treat any secondary brain insults and intracranial hypertension along with the
preservation of cerebral perfusion pressure (CPP) and optimization of cerebral

oxygenation. The deathly triad of acidosis, hypothermia and coagulopathy has a
major deleterious effect on body functions.5
There are specific indications for admission of TBI patients in intensive care
unit (ICU), which include (but not restricted to) severe TBI, hemodynamically
unstable patients and those not awakened or extubated following surgery,
especially if the patient was fully conscious preoperatively. The monitoring of
blood pressure (BP), SaO2, capnometry and intracranial pressure (ICP) monitoring
(if available) should be continued during transport to ICU. The protocol-based
management within a specialist neurocritical care unit involving neurosurgeons,
neurointensivists and neuroimaging specialists has better outcome.6-8
Assessment and Resuscitation

After arrival of such a patient in the ICU, the intensivist needs to quickly take the
following steps:
• Initial assessment and concurrent resuscitative efforts proceeding to CTLS in
ABCDE succession.
• Provide complete and rapid physiological resuscitation achieving sustained
euvolemia.
• Provide for optimal oxygenation and ventilation.
• Maintenance of BP and cerebral perfusion pressure (CPP).
Along with above protocols, physical examination is necessary for overall
evaluation of mental and physical status:
• Examination of head and cranial nerves for lateralizing signs like dilated or
sluggish pupil(s)
• Extremities
– Uni/bilateral weakness
– Posturing
- Flexor-decorticate
- Extensor-decerebrate
– Associated injuries.
To assess the severity of injury on admission as well as to follow the prognosis,
a scoring is mandatory. Among the various scoring modalities glasgow coma scale
(GCS) is the most useful one, as it also has a prognostic significance in predicting
outcome (Table 17.1).9 Motor part of GCS has the greatest predictive ability. It
should be done at first contact but is best done in emergency room after initial
resuscitation, and as soon as the patient reaches the ICU.
Radiological Investigations
Radiological modalities are required for further evaluation. Among them, the most
common is computerized tomography (CT) scan. However, magnetic resonance
Table 17.1 GCS based grading of TBI

≤8 Severe injury
9–12 Moderate
13–15 Mild
Critical Care in Head Injured Patients 201
imaging (MRI) has emerged in recent years as a more sensitive imaging modality
in TBI patients. If available, the predominance of cellular edema in TBI patients
can be measured dynamically by diffusion weighted MRI.10
Indications of CT Scan
i. Canadian CT Head Rule11: CT head is only required for minor head injury
patients with any one of these findings:
I. High risk (for neurological intervention)
• GCS score <15 at 2 hours after injury
• Suspected open or depressed skull fracture
• Any sign of basal skull fracture
• Vomiting ≥ 2 episodes
• Age ≥ 65 years.
II. Medium risk (for brain injury on CT)
• Amnesia before impact ≥ 30 min
• Dangerous mechanism (pedestrian, occupant ejected, fall from elevation).
ii. New Orleans Rule for head CT12: Computed tomography is required for patients
with minor head injury with any one of the following findings. The criteria apply
only to patients who also have a glasgow coma scale score of 15.
• Headache
• Vomiting
• Older than 60 years
• Drug or alcohol intoxication
• Persistent anterograde amnesia (deficits in short-term memory)
• Visible trauma above the clavicle
• Seizure.
iii. Catch Rule: Indications of CT head in children with head injury13
I. High risk (need for neurologic intervention)
• GCS <15–2 hours after injury
• Suspected open or depressed skull fracture - Sensitivity 100%
• History of worsening headache - Specificity 70.2%
• Irritability on examination - Up to 30.3% require a CT
II. Medium risk (brain injury on CT scan)
• Any sign of basal skull fracture - Sensitivity 98.1%
• Large, boggy hematoma of scalp - Specificity 50.1%
• Dangerous mechanism of injury - Up to 51.9% require a CT
Monitoring
Continuous monitoring for the early detection and diagnosis of secondary brain
insults (both systemic and intracranial) has resulted into a significant reduction
in mortality and morbidity. Recommended monitoring modalities are divided
into general and specific monitorings.
General monitoring Specific monitoring

• ECG, pulse oximetry, EtCO2 • ICP
• Arterial BP, CVP • SjvO2
• Temperature, urine output • PbtO2
• ABG, serum electrolytes and osmolality • Cerebral microdialysis
• Cardiac output monitoring (invasive/non- • Transverse cerebellar diameter (TCD)
invasive; indicated in hemodynamically • Near-infrared spectrometry (NIRS)
unstable patients, unresponsive to fluids • Brain temperature
and vasopressors) • EEG
• C T scan
Ventilatory Support
Mechanical ventilation is required in TBI patients, when the GCS is <8 or the
patient is unable to maintain adequate respiration.14 Patients with TBI involving
thalamus, hypothalamus, medulla or vagus nerves may require ventilatory
support. They may also develop neurogenic pulmonary edema necessitating
ventilatory support. The goal of mechanical ventilation is to maintain an
arterial pO2 above 11 kPa and an arterial pCO2 between 4.5 and 5 kPa.15 Positive
end expiratory pressure (PEEP) has beneficial role in case of hypoxemia. But
application of PEEP may increase the intrathoracic venous pressure resulting
in an unacceptable increase in ICP. In such cases, PEEP be reduced or better
avoided.16 Permissive hypercapnia should also be avoided as an increase in pCO2
level causes cerebral vasodilation, which results in an increase in ICP. The specific
protocols to be taken care of during mechanical ventilation are to avoid hypoxia
(SaO2<90%, or PaO2<60 torr). Ordinarily, hyperventilation within the initial
24 hours should be avoided in severe TBI, as it can compromise further an already
compromised cerebral perfusion.17 In any case, prophylactic hyperventilation to
PaCO2 <25 mm Hg must always be avoided.17
Hemodynamic Support
Hemodynamic instability is a common finding in severe TBI patients due to
intravascular volume depletion or brainstem injuries.18 The global or focal loss
of the capacity for vascular autoregulation and hypotension (MAP ≤65 or SBP
≤ 90 torr) is often present in severe TBI. In these patients, persistent hypotension
is proven to be a major determinant and an independent predictor.18 Hypotension
causes a reduction in cerebral blood flow and below a threshold value, results in
cerebral ischemia. It should be avoided at all costs and aggressively managed if
occurs.19 On the other hand, episodes of hypertension can increase vasogenic
edema with a detrimental increase of ICP and an aggravation of secondary
systemic brain insult.20 However, as hypertension may also be present as a
physiological response to a reduced cerebral perfusion, it should not be treated
unless a cause has been excluded or treated, Active treatment is required only if
SBP > 180–200 mm Hg or MAP > 110–120 mm Hg.
Intracranial Pressure Monitoring

Though there are certain dilemma in the BTF guidelines to make ICP monitoring
a standard of treatment, mainly due to lack of adequate data, yet the guidelines
for ICP monitoring suggest different indications.
• Severe TBI with abnormal CT scan, hematoma, contusion, edema or

compressed basal cisterns.
• Severe TBI with normal CT scan if age >40 years, abnormal posturing or
SBP <90 mm Hg.
• All salvageable patients with moderate-severe TBI.
Insertion of a ventricular catheter and connecting it to an external strain
gauge is the most accurate and reliable technique of ICP monitoring. It has seen
that patients with severe head injury have a poorer prognosis with high ICP in
comparison to those patients with a normal ICP. The critical ICP level above which
immediate action is mandatory is 20 mm Hg. In situations where ICP rises above
the threshold level, following measures are taken to minimize the ICP. Proper
head up positioning, adequate sedation and muscle relaxation, maintenance of
ventilation and CO2, infusion of mannitol and control of seizure and temperature.
The role of ICP monitoring is important as cerebral ischemia is considered to be
the single most important secondary insult affecting the outcome. The CPP (MAP
minus ICP or CVP, whichever is higher), when maintained to a minimum value
of 60 torr, substantially reduces mortality and improves quality of survival.17 In
patients where CPP is maintained above 60–70 torr along with fluid resuscitation
or induced moderate systemic hypertension, incidences of intracranial
hypertension, morbidity, or mortality is decreased. If the CPP is < 70 mm Hg then
judicious use of fluids and vasopressors should be given as there is substantial
risk to develop ARDS.17
Analgesia and Sedation

The analgesic or sedative drug used should preferably have a rapid onset and
offset, can be easily titrated, with no active metabolites, have anticonvulsant
effect, able to lower ICP and cerebral metabolic rate for oxygen (CMRO2), preserve
neurologic examination and most importantly lack deleterious cardiovascular
effects. The primary aim of analgesia and sedation is to minimize pain, anxiety
and agitation. An optimal analgesia facilitates mechanical ventilation, so that the
cerebral metabolic rate of oxygen consumption can be minimized. In addition,
adequate sedation and analgesia minimizes the rise of ICP with minimal effects
on cerebral hemodynamics in adequately resuscitated patients. Sedation is
best provided by anesthetic agents such as midazolam, propofol, thiopental,
etc. whereas analgesia is provided with NSAIDs, acetaminophen or infusion
of opioids, such as remifentanil, fentanyl or morphine. Bucking, coughing or
straining may increase ICP for which neuromuscular blockade may be given
as boluses or infusion. Often a non-depolarizing muscle relaxant, such as
vecuronium or rocuronium is preferred.21
Fluid Administration
For initial resuscitation, 0.9% saline which is slightly hypertonic is widely
accepted. Lactated Ringer’s solution is slightly hypotonic, so it is used with
caution. Fresh whole blood and products are required to avoid large volume
crystalloid administration or in massive hemorrhage/ongoing blood loss.
If required, an alpha agonist may be used to maintain blood pressure and
hemodynamic stability. Furthermore, hypertonic saline (HS) resuscitation has
more benefits, such as faster volume expansion, decreased cerebral edema and
ICP with an increase in regional CBF and improved survival of hypotensive TBI
patients.22 However, it is not without some disadvantages, such as sudden fall of
BP and major increase in sodium level. Furthermore, as the SAFE study reported
an increased mortality with albumin when compared with saline in TBI patients
(33.2% versus 20.4%),23 and subsequent studies also reported an increased
mortality after colloid resuscitation, we often prefer saline over albumin
solutions for resuscitation of TBI patients.24 However, some synthetic colloids
are often included in the resuscitation as well as maintenance fluid regimen of
these patients. In addition, many earlier studies while comparing mannitol with
hypertonic saline (HS) have shown an improvement after both, 20% mannitol
or 3% HS, but without any significant difference between groups. Other studies
reported more sustained and reliable reduction of ICP after 7.5% HS, when
compared to 20% mannitol.25 However, we need more randomize controlled
trials to be able to know the difference, if any, between mannitol and HS.
Temperature Control
Hyperthermia is shown to have deleterious effect on prognosis of severe TBI
patients so fever should be aggressively controlled and treated. In earlier studies,
hypothermia was being reported beneficial in TBI with severe intracranial
hemorrhage (ICH).26 In some other studies also significant outcome has been
observed with moderate hypothermia of around 33°C, which was also associated
with significantly improved outcome at 3 and 6 months postinjury.27 However,
the effectiveness of this therapy has generally been inconsistent in subsequent
studies. In NABIS trial, a lack of effect of hypothermia was demonstrated.28 So,
the general dictum is to use only mild hypothermia that too only in refractory ICP.
Antiseizures Prophylaxis
Classification of post-traumatic seizures is defined as early (<7 days) or late (after
7 days following injury). According to BTF, prophylactic therapy should be given
to prevent early post-traumatic seizure in TBI patients who are at high risk for
seizures but it has no role in preventing late post-traumatic seizures.17 For the
prophylaxis of early post-traumatic seizures, phenytoin is the recommended
drug. Initially, a bolus dose of 15–20 mg/kg is administered over 30 minutes,
followed by 100 mg IV, three times daily for 7 days. The potential side effects
should be monitored during the antiseizure prophylaxis.
Deep Venous Thrombosis Prophylaxis

Severe TBI patients are at a significant risk of developing venous thromboembolism.
Its incidence is 20% when no prophylaxis is initiated.29 The use of mechanical
thromboprophylaxis such as compression stockings and sequential compression
devices is recommended unless their use is prevented by lower extremity
injuries. Low molecular weight heparin or low dose unfractionated heparin
(UFH) should ordinarily be used in combination with mechanical prophylaxis
if there is no contraindication. Pharmacological prophylaxis has an increased
risk of rebleeding and further expansion of intracranial hemorrhage, so it should
be always discussed with neurosurgeon before starting. In absence of any
contraindications, pharmacologic prophylaxis should be started within 48–72

hours after injury.30
Stress Ulcer Prophylaxis

The incidence of stress ulcers (Cushing’s ulcers) is around 10% in patients of
severe TBI.31 Therefore, an early enteral feeding combined with pharmacological
prophylaxis, such as H2 blockers, proton-pump inhibitors and sucralfate are
recommended to avoid these ulcers.32
Role of Nutrition
Head injury patients are usually in a catabolic state with hypermetabolism and
hyperglycemia. Enteral nutrition is preferred mode of nutrition in such patients.
Parenteral nutrition is used only when enteral route is contraindicated, as there
are complications associated with it leading to an increased rate of mortality.33
There are several advantages of enteral route, as it is safe, cost-effective and
physiological. Other advantages of enteral feeding include preservation of the
immunological gut barrier function and intestinal mucosal integrity, stimulation
of gastrointestinal tract (GIT) functions and reduction of infections and septic
complications. Though BTF has recommended to replace 140% and 100%
of resting metabolic expenditure in non-paralyzed and paralyzed patients
respectively, at the author’s center, it is often restricted to 20–30% lower calorie
intake as suggested in other similar reports.34
Endocrine Disorders
Neuroendocrine derangements after TBI must be diagnosed and addressed on
time, due to their potential contribution to morbidity, and possibly mortality.
Injury to hypothalamo-pituitary axis may lead to panhypopituitarism with
deficiency of growth hormone, gonadotropin, corticotropin and/or vasopressin
causing diabetes insipidus/syndrome of inappropriate antidiuretic hormone
secretion (SIADH). Often in the post acute stage or somewhat later, new
endocrine dysfunctions become apparent in patients suffering from severe
hypernatremia, so precautions must be taken if low sodium solutions or synthetic
antidiuretic hormone is administered, as there are fair chances of developing
fatal cerebral edema after a rapid decrease in serum sodium.35
Damage Control Care

Intensivists must be proactive in diagnosing and taking appropriate measures
to avoid and treat the deathly triad of acidosis, hypothermia and coagulopathy.
To minimize damage, optimize cardiac output and institute lung protective
ventilatory measures. In addition, patient’s position, pain, anxiety and nutritional
support must be taken care and appropriate antibiotics started.
Indications for Surgery

If a patient has an extradural hematoma (EDH) > 30 mL in volume, comatose
patients with an acute EDH, patients with clot thickness >10 mm or a midline
shift of >5 mm on CT should be taken for surgical evacuation. In patients with an
intractable intracranial hypertension where medical management fails to resolve

regardless of GCS score decompressive craniectomy and hemicraniectomy are
indicated. However, the overall outcome of such surgical interventions is not so
impressive. Studies have shown a favorable outcome in severe TBI patients at one
year in around 25% of patients.36 On the other hand, other studies have proved
that inspite of decreased intracranial pressure and length of stay in the ICU after
surgery, overall outcome is not so favorable.37 However, most neurosurgical units
do urgent decompressive craniectomy in most such patients.
Other Considerations
Severe blood loss can result in anemia, which can lead to secondary systemic brain
insult due to cerebral hypoxemia. All efforts must be made to avoid anemia due
to hemorrhage. Whenever indicated, as per the recommendations, tranexamic
acid (CRASH-2 trial) should be administered as cerebral damage may cause
coagulopathy due to presence of thromboplastin in brain tissue.38 In cases where
coagulopathy is detected or feared, especially in presence of a traumatic ICH,
corrective measures should be undertaken with blood products as appropriate
(Plasma : Platelet : RBC= 1:1:1).
Predicting Outcome
The prediction and prognosis of outcome is necessary in critically ill TBI
patients. Few theories have been proposed for patient’s outcome after severe TBI.
Among them, a relatively simple prognostic model is based on seven predictive
baseline characteristics, including age, motor score, pupillary reactivity, hypoxia,
hypotension, CT findings and traumatic subarachnoid hemorrhage (SAH). The
prediction in such patients of severe to moderate TBI after 6 months is predicted
more accurately by this model.39 Another predictive model based on age >60
years, absence of light reflex, presence of extensive SAH, ICP, and midline shift
has been shown to have high predictive value and has been recommended for
decision making, review of treatment, and family counseling.40
CONCLUSION
The management of severe TBI requires meticulous and comprehensive
intensive care that includes multimodal, protocolized approach. This involves in
instituting careful hemodynamic support, respiratory care, fluid management,
aimed at preventing secondary brain insults, maintaining an adequate CPP, and
optimizing cerebral oxygenation and other aspects of therapy. The care requires
a multidisciplinary team approach including neuro-intensivist, neurosurgeon,
respiratory therapist, nutritionist and other members of the medical team. While
the management can be challenging, it is by all means rewarding, considering
that the most victims are relatively young and the problem has a significant socio-
economic impact.
KEY POINTS
• Traumatic brain injury (TBI) contributes to increased incidence of morbidity and
mortality following road traffic accidents and other violent injuries. It is a major cause
of death in young adults and children and has a significant socioeconomic impact.
• The management of severe TBI requires meticulous and comprehensive intensive care
that includes multimodal, protocolized approach.
• Guidelines from Brain Trauma Foundation recommend instituting careful hemodynamic
support, respiratory care and fluid management aimed at preventing secondary brain
insults.
• The main focus should be on prevention and treatment of the intracranial hypertension,
secondary brain insult, maintenance of cerebral perfusion pressure and preservation of
cerebral oxygenation.
• Supportive care includes prompt treatment of hypoxemia, hypotension and
hypercarbia. In addition, hyperventilation, tight control blood sugar regime, use of
colloids and parenteral nutritional supplements plays a major role.
• Early sedation and mechanical ventilation should be implemented in more severely
injured patients.
• The care requires a multidisciplinary team approach including neuro-intensivist,
neurosurgeon, respiratory therapist, nutritionist and other members of the medical
team.
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2009;66(2):304-8.
CHAPTER 18
Mechanical Ventilation: Tidal Volume,
PEEP and Recruitment
JV Divatia, Mohd Saif Khan
INTRODUCTION
The adult respiratory distress syndrome was first described in 1967 as severe
respiratory failure accompanied by pulmonary infiltrates.1 The syndrome was
diffuse, occurred heterogeneously in a variety of clinical settings, and manifested
the same complement of symptoms and abnormalities regardless of the source
of the lung injury or even whether or not that source was known. Most patients
with this condition required intubation and ventilatory support to correct the
severe hypoxia. The mortality was high. At autopsy, lungs of patients dying with
ARDS were found to be severely damaged. This syndrome, now termed the
Acute Respiratory Distress Syndrome (ARDS) is currently defined by the Berlin
definition2 as follows:
Timing: Within 1 week of a known clinical insult or new or worsening
respiratory symptoms
Chest imaging: Bilateral opacities—not fully explained by effusions, lobar/
lung collapse, or nodules
Origin of edema: Respiratory failure not fully explained by cardiac failure or
fluid overload. Need objective assessment (e.g. echocardio
graphy) to exclude hydrostatic edema if no risk factor present
Oxygenation: Mild 200 mm Hg ≥PaO2/FIO2 <300 mm Hg with PEEP or
CPAP ≥5 cm H2O; Moderate 100 mm Hg ≥ PaO2/FIO2 <200
mm Hg with PEEP ≥5 cm H2O; Severe PaO2/FIO2 <100 mm
Hg with PEEP ≥5 cm H2O
The current standard of ventilatory management of ARDS has been
summarized in a recent review.3 In this chapter, we will discuss the background
and rationale for these lung-protective ventilation strategies, focusing on tidal
volume and positive end-expiratory pressure (PEEP) settings.
VENTILATOR-INITIATED LUNG INJURY

Conventional Ventilatory Strategy
From the time ARDS was first described, PEEP became a standard intervention to
correct refractory hypoxia. Ventilation was adjusted to maintain the blood gases
within a reasonably normal range, such as PaO2 of 65–80 mm Hg, and PaCO2 of
40–50 mm Hg. High tidal volumes (10–15 mL/kg) produced better oxygenation,
Mechanical Ventilation: Tidal Volume, PEEP and Recruitment 211
and the low compliance seen in these patients meant that considerably high
pressures were generating during mechanical ventilation. Deteriorating gas
exchange required a high minute ventilation to produce adequate CO2 elimination;
this was achieved by a combination of high tidal volume and respiratory rates.
Clinicians and researchers recognized that mechanical ventilation may itself be
responsible for aggravating or worsening lung injury that required initiation of
mechanical ventilation. Barotrauma and oxygen toxicitiy were well known. Over
the years, the approach to ventilation in ARDS underwent a considerable change
as understanding of the nature of lung injury evolved.4
Volutrauma
The first major change in ventilation strategy came with the recognition that high
tidal volumes may damage the lungs. The role of tidal volume was clarified by a
series of classical animal experiments which showed that high tidal volumes that
caused hyperinflation or overdistension of the lungs were more deleterious to
the lung than high pressures generated without high tidal volumes (achieved by
physically limiting chest expansion with an external restrictive band).5 Thus the
concept of volutrauma was introduced, and it was recognized that overdistension
of the alveoli was an important factor in ventilator-induced lung injury (VILI).
Baby Lung
The next big change came when CT scans of chest revealed that unlike what is
seen on the chest X-ray, lung injury in ARDS is non-homogeneous, and basal,
dependent lung regions are more severely affected by edema and consolidation.6
Thus in a lung of a patient with ARDS, there are regions which are non-aerated
(most dependent, Fig. 18.1C), regions that are non-aerated but recruitable
(Fig. 18.1B), and in the non-dependent region, the lung is aerated; these aerated
regions are called “Baby lung” as they constitute about 30% of the total lung
volume and have a normal compliance (Fig. 18.1A). Ventilation of the lungs with
normal tidal volumes causes the tidal volume to be distributed preferentially to
the compliant alveoli, leading to overdistension of the baby lung and volutrauma.
Overdistension of alveoli is recognized by a plateau pressure >30 cm H2O.
Fig. 18.1: The concept of “Baby Lung” in ARDS showing non-homogeneous regions. A:
Aerated region with normal compliance. B: Non-aerated but recruitable region. C: Non-
aerated region
Fig. 18.2: Recruitment and derecruitment of alveoli during mechanical IPPV breath.
Application of PEEP can keep the alveoli inflated and prevent atelectrauma
Shear Stress and Atelectotrauma

It is estimated that at a transpulmonary pressure of 30 cm H2O, the pressure
tending to expand an atelectatic region surrounded by a fully expanded lung
would be approximately 140 cm H2O. Subjecting diseased and collapsed alveoli
to these pressures could directly damage them. Lung injury is more severe in
animals ventilated without PEEP, suggesting that repeated opening and closing of
recruitable lung units (atelectrauma) also damages the lung.7 During a mechanical
IPPV breath, closed alveoli may open up or get recruited with the peak inflation
pressure, only to return to the collapsed or closed state (derecruitment) when the
airway pressure returns to its baseline low level (Fig. 18.2). The alveoli are then
subjected to this cycle of opening and closing of alveoli during the respiratory
cycle is repeated several thousand times per day. Intense shearing forces develop
at the junctions of open alveoli with collapsed or closed alveoli, and result in
extremely high tensions in the thin tissue walls separating junctional alveoli,
and alveolar damage occurs at points where alveolar membrane is tethered to
surrounding tissue.
The application of PEEP could be beneficial by preventing terminal
end-expiratory alveolar collapse and maintaining the alveoli patent throughout
the respiratory cycle, preventing atelectrauma and high shear stresses from
developing. Conversely, insufficient PEEP could lead to worsening of VILI.
Biotrauma
The conventional lung-ventilation strategies have been shown to promote the
release of inflammatory mediators that worsen lung injury and spill over into
the circulation, causing systemic inflammation and progression of the multiple
organ dysfunction syndrome. This is referred to as biotrauma.7,8
Based on the above understanding, prevention of VILI became an important
goal of ventilation in ARDS and ‘lung protective ventilation (LPV)’ strategies was
devised. This included:
Preventing alveolar overdistension

limit tidal volume 4–6 mL/kg
limit plateau airway pressure (Pplat) < 30 cm H2O
Prevent atelectrauma with appropriate PEEP
In addition, the open lung strategy aims to recruiting collapsed lung units in
the most dependent lung zone using transient application of high pressure and
keeping them open using appropriate PEEP.
TIDAL VOLUME IN ACUTE RESPIRATORY DISTRESS SYNDROME

The twin concepts of volutrauma and the baby lung laid the foundations for
reducing tidal volumes in ventilating patients with acute respiratory distress
syndrome (ARDS). The National Institutes of Health-sponsored Acute
Respiratory Distress Syndrome Network conducted a trial to determine whether
ventilation with lower tidal volumes would improve clinical outcomes.9 Patients
were randomized to receive traditional ventilation protocols (initial tidal volume
of 12 mL/kg of predicted body weight and plateau pressure ≤50 cm of H2O) or
ventilation with a lower tidal volume (6 mL/kg of predicted body weight and a
plateau pressure ≤30 cm of H2O). The trial was halted after enrollment of 861
patients. Mortality was lower in the group treated with lower tidal volumes than
in the group treated with traditional tidal volumes (31.0% vs 39.8%, P = 0.007).
The plateau pressure (i.e., the pressure during an end-inspiratory pause; Pplat)
was the physiological correlate of overdistension. The normal lung is maximally
distended at a transpulmonary pressure between 30 and 35 cm of water, and
higher pressures cause overdistention. In volume controlled ventilation, it
became necessary to limit the tidal volume and to maintain the plateau pressure
within safe limits.
Tidal volumes are important in that they determine the degree of distension
of the alveoli. Pplat > 30 cm H2O implies overdistension; hence tidal volumes
should be titrated to maintain Pplat below 30 cm H2O. Tidal volumes limited to 6
mL/kg should be be used even if the Pplat is < 30 cm H2O. If the Pplat is > 30 cm H2O,
tidal volume may need to be reduced further.
Optimal Tidal Volume in Acute Respiratory Distress Syndrome9

Set initial tidal volume to 8 mL/kg of predicted body weight (PBW). Then over 2 to
3 hours, tidal volume (VT) is gradually reduced to 7 mL then 6 mL/kg of PBW. The
predicted body weight is calculated as follows:
For men, PBW = 50.0 + 0.91 (height in centimeters – 152.4);
For women, PBW = 45.5 + 0.91 (height in centimeters – 152.4).
Assess plateau airway pressure, which should be maintained less than 30
cm of water; if this target is exceeded, the tidal volume should be reduced to a
minimum of 4 mL per kilogram of predicted body weight. It should be noted that
the true distending force of the lung is the transpulmonary pressure (PTP), which
is the difference between airway plateau pressure and the intrapleural pressure.
Thus in case of a stiff chest wall (for example in obesity, ascites), while airway
pressure is elevated, so is the pleural pressure, and the transpulmonary pressures
are not elevated. There is no alveolar overdistension as a proportion of the airway
pressure is dissipated in moving the chest wall. A higher Pplat can be tolerated
well in these patients. Thus Pplat < 30 cm H2O may be inadequate in some obese
patients with ARDS. Measurement of pleural pressure by esophageal manometry
and calculating the PTP is considered superior to that of plateau pressure.10
However, due to invasiveness and technical issues, esophageal manometry is not
used in routine clinical practice.
Implications of Using Low Tidal Volumes

The immediate problem is that of hypoventilation and hypercapnia. However, a
high PaCO2 is acceptable in preference to a high tidal volume that will result in
overdistension.11 Minute ventilation can be increased by increasing the respiratory
rate. In the ARDS Net trial, the rate could be increased to 35 per minute. By virtue
of their stiff lungs, patients with ARDS can tolerate a rapid frequency without
gas trapping. If, however, severe hypercapnia results in increased intracranial
pressure, depressed myocardial contractility, pulmonary hypertension, and
depressed renal blood flow, the pressure and volume targets can be exceeded.
In fact, patients with raised intracranial tension, circulatory instability and
pulmonary hypertension are not candidates for permissive hypercapnia. Other
disadvantages include increased sedation requirements,12-14 increased collapse
of lung tissue (atelectrauma)15 and risk of patient-ventilator asynchrony16
POSITIVE END-EXPIRATORY PRESSURE

Positive end-expiratory pressure (PEEP) helps in correcting refractory
hypoxia seen in ARDS by reducing intrapulmonary shunt. This is achieved by
increase in the mean airway pressure, alveolar recruitment and prevention of
end-expiratory collapse. It also prevents unstable surfactant monolayers in
alveoli. By maintaining alveoli open throughout respiratory cycle, PEEP reduces
the potential for VILI. Collapsed, consolidated basal regions can be opened or
recruited by a high inflating pressure, and can be maintained open by a high
PEEP. However differences in regional compliances mean that pressures that
recruit or hold open alveoli in some regions may overdistend alveoli in other
regions. Further overdistension of these alveoli will occur due to peak inspiratory
pressure. This is more likely with focal disease, and less likely with diffuse
disease.17 The hemodynamic effects of PEEP are well known, and include reduced
cardiac output due to raised intrathoracic pressure and decreased venous return,
increased pulmonary vascular resistance, right ventricular strain or failure, septal
shift to left, reduced left ventricular compliance, and reduced cerebral perfusion
pressure.
The challenge is, therefore, to apply the right level of PEEP, one that will
optimize oxygenation, recruit alveoli and prevent end-expiratory alveolar
collapse without resulting in overdistension and hemodynamic instability.
How should PEEP be Applied?

Oxygenation Criteria
The simplest and perhaps the commonest method of titrating PEEP is according
to oxygenaton criteria. The level of PEEP that allows the FiO2 to be maintained
<0.6, or that level which produces acceptable oxygenation at a given FiO2 is
applied. In the ARDS Net study9, patients received a fixed combination of FiO2
and PEEP, and both FiO2 and PEEP were titrated upward or downward to achieve
the oxygenation goal according to a fixed protocol (Table 18.1).
Best Compliance
Alternatively, the PEEP level that results in the best static compliance can be
used. To obtain this ‘best PEEP’, static compliance is calculated for increasing
levels of PEEP during volume controlled breaths. Again, the plateau pressure is
noted during an inspiratory hold, and auto-PEEP is noted during an expiratory
hold. The static compliance (Cstat) is calculated as—
Cstat = Tidal volume/[Pplat – (set PEEP + auto-PEEP)]
Respiratory Mechanics to Determine Positive End-expiratory Pressure

A sophisticated method of selecting the best level of PEEP using respiratory
mechanics is to use the pressure-volume curve of the respiratory system
(Fig. 18.2).
The static PV loop (pressure-volume curve) is a plot of tidal volume against
the plateau pressure, obtained under conditions where flow resistance is
eliminated. This is the airway pressure measured during a set inspiratory pause
of 0.5–2 seconds or when the inspiratory hold maneuver is applied. In normal
individuals, the inspiratory limb of the curve has a sigmoid shape (Fig. 18.3). It is
linear in its initial part. In the lower section (A) the compliance is low until a lower
inflection point has been reached. The compliance then rises rapidly and linearly,
continuing in a straight line (B) once the lung opening pressure (lower inflection
point) has been exceeded. If the lung reaches the limits of its compliance, the rise
in the pressure per volume increase becomes bigger again, indicating decreased
compliance beyond the upper inflection point (C). It is generally accepted that
ventilation should take place within the linear compliance area (B). The lower
inflection point can be overcome by setting a PEEP just above the lower inflection
point pressure. This will help prevent expiratory collapse of alveoli and help in
keeping the lung open. The tidal volume to be delivered is that between the lower
and upper inflection points. The plateau pressure limit is that corresponding to
the upper inflection point. Ventilation with higher tidal volumes or pressures
would result in alveolar overdistension.
Table 18.1 FiO2 and PEEP settings in the ARDS network study8
Arterial oxygenation goal: PaO2 = 55-80 mm Hg or SpO2 = 88-95%
FiO2 PEEP FiO2 PEEP
0.3 5 0.7 12
0.4 5 0.7 14
0.4 8 0.8 14
0.5 8 0.9 14
0.5 10 0.9 16
0.6 10 0.9 18
0.7 10 1.0 20–24
Fig. 18.3: Static pressure-volume curve of the respiratory system
The expiratory limb of the loop can be used to determine the PEEP required
to keep a recruited lung open. The expiratory point of maximum curvature is a
good marker of the onset of derecruitment. If PEEP is aimed to completely avoid
derecruitment, this point should be the target. However, this is associated to
hyperinflation of healthy areas. Alveolar derecruitment with PEEP decrements
occurs over a wide range of pressures till PEEP. Thus the static P-V loop enables
key elements of the “open lung ventilation” strategy to be set scientifically.
How to Obtain the PV Curve?

The theoretical, technical and practical aspects of the PV loop were recently
summarized by Lu and Rouby.18 Methods that can be used in clinical practice
include:
• Inspiratory occlusion method:19 During volume controlled ventilation, at set
PEEP of zero, varying tidal volumes are delivered, and for each tidal volume,
the plateau pressure is noted while an inspiratory hold is performed. Tidal
volumes varying between 50 and 1000 mL are applied in random sequence.
Thus a graph consisting of tidal volumes and their corresponding plateau
pressures is plotted, and the inflection points noted. The patient does not need
to be disconnected from the ventilator. 100% oxygen must be given before and
during the procedure. It is not uncommon for oxygenation to drop during
these maneuvers in patients with severe ARDS. Also, an expiratory hold must
be performed to determine the auto-PEEP. Auto-PEEP, if present, must be
deducted from the plateau pressure measured.
• Quasistatic methods:20,21 The PV loop can be plotted during a single breath
using special settings and graphic software. In order to eliminate flow-related
resistance during a breath, is essential to inflate the lungs at a very low constant
flow rate (<9 L/m). Since the presence of even a low flow rate will introduce
a small element of flow-resistance, this is called a quasi-static measurement.
Such quasistatic measurements have been shown to correlate well with static
measurements, and are appropriate for clinical use. A volume controlled
breath of 1 liter is given at a flow rate of 9 L/min, i.e. an inspiratory time >6
seconds, with PEEP set to zero. Several ventilators now have the capability to
move cursors to determine the relevant inflection points, tidal volumes and
plateau pressures.
Setting PEEP without PV Loops

In some patients, it may be difficult, impossible or dangerous to plot PV curves,
while in others, there may be no clear inflection point at all. In such cases, a PEEP
of 16 cm H2O has been used.22
Transpulmonary Pressure Measurement to Set PEEP

Esophageal balloon directed estimation of pleural pressures is used to calculate
transpulmonary pressures and guide PEEP titration. The PEEP is set so that
the transpulmonary pressure is greater than zero at end-expiration, and is
less than 25 cm H2O during inspiration, while using a tidal volume of 6 mL/kg
PBW. Talmor et al showed that compared with the standard FiO2-PEEP table-
based tiration of PEEP, a ventilator strategy using esophageal pressures to
estimate the transpulmonary pressure significantly improved oxygenation and
compliance.23 The Esophageal Pressure-Guided Ventilation 2 Trial (EPVent2)
is currently examining the outcomes of mechanical ventilation directed at
maintaining a positive transpulmonary pressure in patients with moderate-to-
severe ARDS, as compared to standard treatment.24
Newer technologies such as lung ultrasound and electrical impedance allow
visualization of ventilation and have been used to titrate PEEP. However, lung
ultrasound cannot diagnose overdistension and EIT is still evolving, and is not
widely available for the clinical use.25
The easiest approach to select PEEP might be according to the severity of
the disease: 5–10 cm H2O PEEP in mild ARDS, 10–15 cm H2O PEEP in moderate
ARDS, and 15–20 cm H2O PEEP in severe ARDS.26
Is High PEEP Necessary?

The level of PEEP, which is the least injurious but therapeutic for such patients
still needs to be determined. In patients with greater lung recruitability, the
beneficial impact of reducing the amount of opening and closing lung tissue by
increasing PEEP appears to outweigh the potentially harmful effects of alveolar
overdistension.27 Table 18.2 is a FiO2-PEEP table set to deliver higher PEEP levels.28
A systematic review29 which synthesized data (n = 2,229) from three trials
comparing a low-PEEP versus a high-PEEP strategy in 2010, showed no overall
difference in mortality with high PEEP. However, a significant mortality benefit of
using higher PEEP level was seen in the subgroup with PaO2/FiO2 <200 mmHg,
Table 18.2 Higher PEEP – FiO2 settings

FiO2 PEEP
0.3 5–10
0.4 10–18
0.5 18–20
0.6 20
0.7 20
0.8 20–22
0.9 22
1.0 22–24
and a trend to worse outcome with high PEEP levels in patients with PaO2/
FiO2 < 300 but >200 mmHg. This suggests that in patients with mild ARDS and
therefore, less lung recruitability, high PEEP may be detrimental, probably due to
overdistension.
Predicting Adverse Responses to PEEP

Regional differences in compliance can result in PEEP leading to overdistension
in certain areas of the lung. It would be useful to be able to predict in which
patients this is likely to happen. It is believed that patients with ARDS from with
pulmonary causes, such as pneumonia, are less likely to benefit from high PEEP
than are those with non-pulmonary causes, such as intra-abdominal sepsis or
extrathoracic trauma.30 The presence of focal or patchy disease rather than
diffuse disease on the CT scan indicates a poor response to PEEP.17
High PEEP may also increase pulmonary vascular resistance and cause
acute cor pulmonale. Risk factors for the development of acute cor pulmonale
include pneumonia as a cause of ARDS, driving pressure >18 cm H2O, PaO2/FiO2
ratio ≤150 mmHg, and arterial carbon dioxide partial pressure ≥48 mm Hg.31 It
has been suggested that clinicians use a right ventricular protective approach
to mechanical ventilation: monitor RV function using echocardiography in
moderate to severe ARDS patients, and to use the prone position if increasing
PEEP results in right ventricular strain.32
CONCEPT OF DRIVING PRESSURE

Driving pressure (ΔP = Pplat – PEEP) may be more strongly associated with
survival than tidal volume (VT) or PEEP. The tidal volume normalized to
functional lung size is more logical than VT set based on predicted lung size.
The respiratory-system compliance (CRS) is strongly related to the volume of
aerated remaining functional lung. Mathematically, driving pressure is equal to
VT/ CRS. Ventilatory strategy using lower plateau airway pressures (Pplat), lower
tidal volumes (VT), and PEEP can all improve survival in patients with ARDS, but
the clear impact of each component on outcome was not determined. Amato
et al. hypothesized that the driving pressure would be a better predictor of survival
than VT or PEEP alone in ARDS.33 They retrospectively analyzed the data from
all the ARDS Network trials. They found that changes in tidal volume or PEEP
that decreased driving pressure were beneficial, while ventilator adjustements
that cause the driving pressure to increase were detrimental. Individual changes
in VT or PEEP were independently associated with survival only if the changes
led to reductions in ΔP. Further, in a retrospective analysis of the study that used
transpulmonary pressure to set PEEP, it was found that utilizing PEEP titration
to target positive transpulmonary pressure via esophageal manometry causes
both improved elastance and driving pressures.34 Treatment strategies leading to
increased respiratory system compliance and transpulmonary driving pressure
at 24 hours may be associated with improved 28-day mortality.
RECRUITMENT MANEUVER
It may be possible to open up or ‘recruit’ at least some of the collapsed areas
by the use of continuous or repetitive application of increased levels of
distending alveolar pressure, much higher than that recommended for the
ventilation of patients with ARDS. A recruitment maneuver (RM) is a dynamic,
transient increase in transpulmonary pressure which is directly proportional
to the reopening of lung units. The effectiveness and potential for recruitment
depend on the number of closed alveolar units. Prediction of recruitability using
physiological parameters such as PEEP, PaO2/FiO2 ratio, PCO2 and compliance
is variable.35 In general, patients with early, diffuse ARDS respond well to RMs,
whereas patients with late ARDS (>1 week) or focal ARDS do not. Initially higher
airway pressures (as much as 60 cm of H2O) would be required, later; it may be
possible to maintain it with lower pressures.
Techniques of Recruitment
Recruitment maneuvers are used to open previously closed areas of the lung, and
once opened, must be held open by appropriate PEEP.
The most frequently investigated RM, due to its apparent simplicity, is the
sustained inflation, which consists of pressurizing the airways at a specific level
and maintaining it for a given duration. A common combination is the application
of 40 cm H2O airway pressure for 40 seconds.36
In the stepwise increase in airway pressure followed by decremental PEEP
titration using pressure controlled ventilation, both Ppeak and PEEP are increased,
with the driving pressure fixed at 15 cm H2O. Recruitment starts with a PEEP of
25 cm H2O and Ppeak 40 cm H2O, and continues till Ppeak of 50 cm H2O and
PEEP of 35 cm H2O. This is followed by decremental PEEP titration. Compliance
and oxygenation are measured at each decrement in PEEP. The optimal PEEP is
identified by the best CRS or best oxygenation, and PEEP is set 2 cm H2O above the
optimal level.37
The patient should be monitored for hypotension and fall in oxygen saturation
during the RM. It is also important to emphasize that an RM should be followed
up with an appropriate PEEP level, set in a decremental fashion; otherwise
derecruitment may occur. A successful RM is recognized by the presence of all of:
• Improved oxygenation
• Increased respiratory system compliance
• Decreased PaCO2
Efficacy and Safety of RM

RM should not be routinely used in stable ARDS patients, but may be used in
case of life-threatening hypoxemia. A recent meta-analysis38 showed that RMs
may decrease the mortality of patients with ARDS without increasing the risk for
major adverse events. However, the evidence is not definitive as several other
interventions were used along with RMs. RMs should be applied after tracheal
suctioning39 or patient disconnection. However, there are concerns regarding
the safety of RM in terms of hypotension, barotrauma and a possible increase
in intracranial pressure.40,41 A trial with high methodological rigor is underway
to evaluate the 28-day survival of ARDS patients subjected to maximum alveolar
recruitment associated with open lung ventilation using PEEP titrated to the
static compliance of the respiratory system (ART strategy).42
PRONE POSITION
The prone position also allows closed aveloli in the previously dependent lung
regions, and results in more homogeneous distribution of ventilation. This has
beneficial effects on gas exchange and respiratory mechanics. It also results in
less injurious ventilation, and reduces right ventricular strain.43 The PROSEVA
trial has firmly established that the prone position improves outcome in patients
with ARDS and PaO2/FiO2 ratios ≤150.44
LOW TIDAL VOLUMES AND PEEP IN PATIENTS

WITH NORMAL LUNGS?
Several studies have suggested that protective lung ventilation strategies
including use of low tidal volumes should be in patients who do not have ARDS
but receive mechanical ventilation. These include patients ventilated during
general anesthesia for major surgery, postoperative ventilation and mechanical
ventilation in patients with normal lungs. Prompt development of densities in
dependent regions of both lungs occurs immediately after induction of general
anesthesia, both during spontaneous breathing and after muscle paralysis.45
15–20% of the lung is collapsed after general anesthesia, before any surgery
has been done. These areas remain collapsed for several days postoperatively,
and may become foci of infection and contribute to postoperative pulmonary
complications (POPCs).45 Traditionally, high tidal volume ventilation without
PEEP is used to overcome atelectasis; however this could result in volutrauma
in some patients. Low tidal volumes without PEEP can result in lung injury due
to atelectrauma. An injurious pattern of ventilation along with other hits during
surgery, including inflammation, compression of the lung during surgery, blood
transfusion and hypoperfusion can result in POPCs and ARDS.46,47 Futier et al.
conducted a large, randomized controlled trial in 400 adults at intermediate
to high risk of pulmonary complications after major abdominal surgery.48 The
non-protective ventilation group received conventional ventilation with VT 10–12
mL/kg PBW, no PEEP or recruitment maneuvers, compared to the Protective
Ventilation group that received VT 6–8 mL/kg PBW, PEEP 6–8, and RM every
30 min after intubation. There was a significant reduction in the composite
outcome of major pulmonary and extrapulmonary complications within the
7 postoperative days for the Protective Ventilation group (10.5% vs 27.5%), as
well as in the need for noninvasive ventilation or tracheal intubation (5% vs.
17%). A Cochrane review49 found that low tidal volumes decrease the need for
postoperative ventilatory support. Unfortunately they defined low tidal volume
as VT <10 mL/kg. A systematic review of 15 randomized controlled trials (2,127
patients) found significantly reduced incidence of POPCs in patients receiving
protective ventilation compared to those receiving conventional ventilation
(8.7% vs. 14.7%, p < 0.01). It concluded that further trials are necessary to define
the role of intraoperative higher PEEP to prevent POPCs after major abdominal
surgery.50 Based on the current evidence, the use of low VT, moderate PEEP and
recruitment maneuvers during mechanical ventilation and general anesthesia
may reduce POPCs after major surgery.
KEY POINTS
• L ow tidal volume ventilation is efficacious in preventing ventilator-associated lung
injury due to volutrauma
• PEEP may prevent the damage produced by the repetitive opening and closing of the
small airway and alveoli.
• Mechanical-ventilation strategies that use Pplat ≤30 cm H2O), VT ≤6 mL/kg PBW, and
higher positive end-expiratory pressure (PEEP) can improve survival in patients with
ARDS.
• P plat is not a true representative of alveolar overdistension. The true distending force of
the lung is the PTP.
• Individual changes in V T or PEEP were independently associated with survival only if the
changes led to reductions in the driving pressure (ΔP = V T/CRS).
• The easiest approach to select PEEP might be according to the severity of the disease:
5–10 cm H2O PEEP in mild ARDS, 10–15 cm H2O PEEP in moderate ARDS, and 15–20 cm
H2O PEEP in severe ARDS.
• The open lung ventilation approach involves recruitment maneuvers and increasing
the level of PEEP in combination with low tidal volume ventilation.
• The prone position results in greater recruitment of alveoli and improves outcome in
moderate to severe ARDS.
• Patients without ARDS receiving mechanical ventilation, including those undergoing
major surgery under general anesthesia, may benefit from low tidal volume ventilation,
moderate PEEP and recruitment maneuvers.
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failure. Automated low flow inflation versus occlusion. Am J Respir Crit Care Med.
1997;155:1629-36.
21. Lu Q, Vieira S, Richecoeur J, et al. A simple automated method for measuring
pressure-volume curve during mechanical ventilation. Am J Respir Crit Care Med.
1999;159:275-82.
22. Amato MBP, Barbas CSV, Medeiros DM, et al. Effect of a protective-ventilation strategy
on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998;338:347-54.
23. Talmor D, Sarge T, Malhotra A, et al. Mechanical ventilation guided by esophageal
pressure in acute lung injury. N Engl J Med. 2008;359:2095-104.
24. Fish E, Novack V, Banner-Goodspeed VM, Sarge T, Loring S, Talmor D. The esophageal
pressure-guided ventilation 2 (EPVent2) trial protocol: a multicentre, randomised
clinical trial of mechanical ventilation guided by transpulmonary pressure. BMJ Open.
2014;4(9):e006356.
25. Lu Q. How to assess positive end-expiratory pressure-induced alveolar recruitment?
Minerva Anestesiol. 2013;79:83-91.
26. Gattinoni L, Carlesso E, Cressoni M. Selecting the ‘right’ positive end-expiratory
pressure level. Curr Opin Crit Care. 2015;21:50-7.
27. Caironi P, Cressoni M, Chiumello D et al. Lung opening and closing during ventilation
of acute respiratory distress syndrome. Am J Respir Crit Care Med. 2010;181:578-86.
28. Chiumello D, Cressoni M, Carlesso E, et al. Bedside selection of positive end-expiratory
pressure in mild, moderate, and severe acute respiratory distress syndrome. Crit Care
Med. 2014;42:252-64.
29. Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure
in patients with acute lung injury and acute respiratory distress syndrome: systematic
review and meta-analysis. JAMA. 2010;303:865-73.
30. Gattinoni L, Pelosi P, Suter PM, Pedoto A, Vercesi P, Lissoni A. Acute respiratory distress
syndrome caused by pulmonary and extrapulmonary disease: different syndromes?
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31. Mekontso-Dessap A, Boissier F, Charron C, et al. Acute cor pulmonale during protective
ventilation for acute respiratory distress syndrome: prevalence, predictors, and clinical
impact. Intensive Care Med. 2016;42:862-70.
32. Vieillard-Baron A, Price LC, Matthay MA. Acute cor pulmonale in ARDS. Intensive
Care Med. 2013;39:1836-8.
33. Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute
34. Baedorf Kassis E, Loring SH, Talmor D. Mortality and pulmonary mechanics in relation
to respiratory system and transpulmonary driving pressures in ARDS. Intensive Care
Med. 2016;42:1206-13.
35. Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute
36. Hartland BL, Newell TJ, Damico N. Alveolar recruitment maneuvers under general
anesthesia: a systematic review of the literature. Respir Care. 2015;60:609-20.
37. Suzumura EA, Amato MB, Cavalcanti AB. Understanding recruitment maneuvers.
38. Suzumura EA, Figueiró M, Normilio-Silva K, et al. Effects of alveolar recruitment
maneuvers on clinical outcomes in patients with acute respiratory distress syndrome:
a systematic review and meta-analysis. Intensive Care Med. 2014;4:1227-40.
39. Maggiore SM, Lellouche F, Pigeot J, et al. Prevention of endotracheal suctioning-
induced alveolar derecruitment in acute lung injury. Am J Respir Crit Care Med. 2003;
167:1215-24.
40. Lim SC, Adams AB, Simonson DA, et al. Transient hemodynamic effects of recruitment
maneuvers in three experimental models of acute lung injury. Crit Care Med.
2004;32:2378-84.
41. Mrozek S, Constantin JM, Geeraerts T. Brain-lung crosstalk: Implications for
neurocritical care patients. World J Crit Care Med. 2015;4:163-78.
42. ART Investigators. Rationale, study design, and analysis plan of the alveolar
recruitment for ARDS trial (ART): study protocol for a randomized controlled trial.
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44. Guérin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory
distress syndrome. N Engl J Med. 2013;36:2159-68.
45. Hedenstierna G, Edmark L. The effects of anesthesia and muscle paralysis on the
respiratory system. Intensive Care Med. 2005;31:1327-35.
46. Futier E, Marret E, Jaber S. Perioperative positive pressure ventilation: an integrated
approach to improve pulmonary care. Anesthesiology. 2014;121:400-8.
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postoperative outcome. Anesthesiology. 2013;118:1254-7.
48. Futier E, Constantin JM, Paugam-Burtz C, et al. A trial of intraoperative low-tidal-
volume ventilation in abdominal surgery. N Engl J Med. 2013;369:428-37.
49. Guay J, Ochroch EA. Intraoperative use of low volume ventilation to decrease
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50. Serpa Neto A, Hemmes SN, Barbas CS, et al. Protective versus conventional
ventilation for surgery: A systematic review and individual patient data meta-analysis.
CHAPTER 19
Palliative and Hospice Care:
Need of the Hour to Improve
Quality and Quantity of Life
Sushma Bhatnagar, Sachidanand Jee Bharti
INTRODUCTION
In the modern era of medical science, the disease demography has changed over
last 2 decades. The noncommunicable diseases like cardiovascular diseases,
cancers, diabetes, renal diseases, respiratory diseases and neurological diseases
are on the rise. This upsurge of chronic illnesses with better treatment gradually
leads to increasing population of patients living with the disease for longer
period of time. With these chronic illnesses, the symptom burden also becomes
predominant over a period of time. Hence, a stage comes in the natural history of
any chronic illness where patients need more support and care than the definitive
treatment.
The word palliative comes from the Latin pallium, ‘to cloak’, meaning
alleviation of the patient’s symptoms.1 As per the World Health Organization
(WHO) definition of palliative care as “an approach that improves the quality
of life of patients and their families facing the problems associated with life-
threatening illness, through the prevention and relief of suffering by means
of early identification and impeccable assessment and treatment of pain and
other problems, physical, psychosocial and spiritual”.2 So, palliative care aims
to improve the outcome of patients through a holistic approach; considering
the physical, psychosocial and spiritual modes of treatment. There is increasing
acceptance of the principles of palliative and supportive care for cancer and non-
cancer patients to provide multidisciplinary symptom management.3
HISTORICAL PERSPECTIVE OF PALLIATIVE CARE

Although palliative care is recognized as a subspecialty few decades back
but its history is as old as Hippocrates of Kos (c.460–c.370 BC). Era of modern
palliative care began with care of terminally ill dying patients. In the late 1950s,
Dr Cicely Saunders first observed that pain is the most predominant symptom in
dying patients. She introduced the concept of ‘total pain’ in context of physical,
psychological and spiritual issues related to disease affecting patients and the
family.4,5
Dr Balfour Mount, a Canadian physician and surgeon, first used the term
‘palliative care’ and is considered to be the father of palliative care. He was the
pioneer to demonstrate that the holistic care of people experiencing physical,
psychological, social, or spiritual distress due to chronic or life-limiting illnesses
could make a lot of difference in their outcome.
Palliative and Hospice Care: Need of the Hour to Improve Quality and Quantity of Life 225
SCOPE OF PALLIATIVE CARE

Palliative care is a multidisciplinary specialty which emphasizes on improving the
quality of life of individuals suffering from chronic debilitating illnesses and their
families. In the last decade, there is a paradigm shift in the concept of palliative
care from last resort treatment option to integration into the management plan in
the early stages of chronic diseases (Fig. 19.1).
COMPONENTS OF PALLIATIVE CARE

The core components of palliative care include:6
• Providing holistic and realistic care within limits of medical ethics
• Assessment and management of physical and psychological symptoms
• Assessment and support for spiritual needs
• Effective communication for setting up of goals of care and assist in decision
making
• Interdisciplinary coordination
• Public education and awareness
• Grief and bereavement care.
World Health Organization (WHO) redefined the concept of palliative care
and integrated it in the treatment plan, irrespective of the disease outcome,
specifying that patients and their families should receive palliative care early
in the course of a disease.7 Recently, a new concept of palliative care has come
up which define ‘palliative care as the person-centered attention to physical
symptoms and to psychological, social, and existential distress and cultural
needs of patients with limited prognosis in order to optimize the quality of life of
patients and their families or friends’.8 Palliative care services are broadly divided
into basic and specialized palliative care.6
Basic palliative care should be provided by all primary and secondary
providers who are involved in treating patients with life limiting and life
threatening illness. They should have basic skills and knowledge of palliative
care. Although providing palliative care is not the primary focus of their work
rather it is a part of patient care.
Fig. 19.1 Integration of palliative care in disease care pathway

Specialized palliative care refers to that provided by palliative care specialists

with appropriate education and training in the field of palliative care. They
should be proficient in managing complex problems and difficult situation which
are not addressed by primary care providers. It needs proper skill and knowledge
to integrate and coordinate with different specialties at right time to provide
complete care of patients and their family.
CORE COMPETENCIES REQUIRED IN PALLIATIVE CARE

Core competencies required in palliative care are:6
• Able to apply the principles of palliative care as per the choice of patient and
family which affirm life and provide support system to encourage an active life
till death without compromising quality of life.
• Competent in managing physical symptoms, anticipation of potential
complications in disease trajectory and offering best possible end of life care
regardless of setting.
• Should acknowledge patients emotions, help in coping and address other
specific psychological issues associated with disease process.
• Helping patients to overcome interpersonal, financial and other social issue
affecting quality of life.
• Offering logical explanation of spiritual quarries such as meaning of life;
why it happens to me, respecting their beliefs, social and cultural taboos and
religious faith.
• Discuss and help family carers to plan short-, medium- and long-term goals
for patient care.
• Able to face ethical challenges and moral dilemmas, take decision keeping
medical ethics intact and involve patients, family and carers in decision
making process.
• Able to lead the team of different specialties involved in patient care with
smooth transition between care setting and strengthening relation between
patient, family and care teams.
• Effective communication skills to deal with difficult situations in palliative
care such as breaking bad news, withholding or withdrawing life prolonging
measures, etc.
• Practice self-care, self-awareness and evidence based medicine.
PALLIATIVE CARE IN INDIA

In 1986, palliative care movement in India started with establishment of Shanti
Avedna Sadan in Mumbai.9 This was further strengthened in 1990s with formation
of Pain and Palliative Care Society in Calicut (PPCS, 1993) and Indian Association
of Palliative Care (IAPC, 1994). In the latter part of 1990s, new palliative care
centers were started in Assam, Chennai, Delhi, Bangaluru and Trivandrum.
Although the Ministry of Health and Family Welfare announced a National
Program for Palliative Care (NPPC) in 2012 but it was not implemented due to
nonallocation of funds. Also, because of limited availability of oral morphine and
legislative issues, this movement never gets momentum at national level.10 Even
though States like Kerala continued its palliative care program with the help of
NGOs and individual efforts.11
But due to continuous efforts and perseverance of institutions, nongovern-

mental organizations (NGO) and dedicated people, Indian Parliament passed the
Narcotic Drugs and Psychotropic Substance (NDPS) Amendment Act in February
2014. This new Act transferred the powers for legislation on essential narcotic
drugs (ENDs) from the State Government to the Central Government.12,13 Finally
in May 2015, the Department of Revenue, Government of India notified the new
State NPPS rule. Since then, all the States would have to follow a uniform rule and
a single governmental approval by a single agency is required for procuring and
dispensing morphine.14
The availability and access to palliative care services is very limited in India.
It has been estimated that <1% Indian population has access to palliative care
services.15 Palliative care in India always means care of cancer patients but
we do not have data for need of palliative care for other chronic debilitating
diseases. Worldwide, access to palliative care is measured indirectly by per capita
consumption of opioids. In the developed world, 3–7.5% of population have
access to opioids for pain relief whereas in India, it is only 0.22%.16,17 This reflects
the paucity and very limited infrastructure available in the field of palliative care.
In a survey conducted by McDermott et al. a total of 139 palliative care and
hospice centers were identified in India with 83 centers alone in the State of
Kerala. Palliative care and hospice centers are mostly run in metro cities, attached
to institutions and with minimum participation from community.18
In developing world like ours where we are still fighting to control the
communicable diseases like tuberculosis, AIDS, malaria and dengue, the upsurge
of noncommunicable diseases (NCD) like cardiovascular diseases, diabetes,
cancer and chronic pulmonary diseases are hitting the drum hard to blow it.19,20
It is estimated that by 2020, the predicted burden of NCD will account for 80%
of global disease burden with majority in developing world.21,22 Palliative care
services in developing world are nonexistent as per need and demand and the
causes are many (Table 19.1).
HOW TO START PALLIATIVE CARE SERVICES?

Palliative care services in developing countries should target to meet the cultural,
spiritual and religious needs of the people without affecting the finances of the
family and economics the country.23 According to WHO model of public health,
it is important to identify organizations that have the potential to become centers
of excellence in their respective fields as in palliative care. But the concept
of palliative care for all can only be achieved by integrating it into the existing
Table 19.1 Causes of unmet needs

• Population burden on healthcare system
• Poverty
• Illiteracy
• Lack of resources
– Human resource
– Funds
• Lack of knowledge, skill and training
• Lack of commitment from government side
healthcare infrastructure at the level from community to tertiary care level. There
must be funding and service delivery system that will provide financial assistant
and manpower resource for conducting palliative care services.
It is important to engage the community through people to people contact,
through role models, through media and administrative leaders. This will help to
identify the need of palliative care for the society.24,25
So, to start the palliative care services, first we have to identify
• The place or institution
• Target population
• Target territory or specific area in each State
• Funding agencies
• NGOs
• Industrial houses willing to help
• Volunteers
• Type of palliative care (inpatient and/or outpatient and/or homecare)
HOW TO IMPLEMENT PALLIATIVE CARE PROGRAM IN INDIA?

In our system of health care, the implementation of palliative care services will
need to be done in phases because of cultural, religious, spiritual and financial
disparity among people. Following things can be done in step wise manner for
implementation of palliative care services in the existing health care system:
• To provide required funds, equipments and medicines to Government
hospitals to start palliative care units.
• To simplify the process of licensing, storage and distribution of opioids and
pain reliving drugs like morphine.
• To start training cells at various levels.
• To train the doctors and nurses.
• To ensure financial provision for the above mentioned activities.
• To include ‘palliative care’ in UG and PG curriculum of medicine, nursing, and
pharmacy.
• To use the media for community awareness and sensitization amongst general
population through role models, prominent personalities in the fields of art,
culture and entertainment.
• Encouragement to provide home based palliative care services.
• To involve private medical institutes.
• Networking with international funding agencies, NGOs and governmental
organizations.
CONCLUSION
The needs in the field of palliative care are immense. The society and the
government have to work together to fulfill these needs and gaps. In country like
India, we have to work at multiple levels considering the population, poverty,
social and cultural diversity with limited resources.26 A successful palliative care
is not possible till we integrate it from the beginning of disease in all forms of
chronic illnesses. Sensitization of primary physician for the need of special
care in patients with chronic disease is corner stone for the implementation of
palliative care. High quality palliative care can only be possible with evidence
based practice. To generate evidences, research in the field of palliative care

is the need of the hour. Institutions, organizations whether governmental or
nongovernmental and commercial houses will have to work collectively to
generate evidences for Indian population in the area of palliative care.
KEY POINTS
• I n the journey of chronic illnesses, it is the right of patient and the family to get palliative
care services as a part of treatment.
• Palliative medicine is an emerging field of medicine in developing world can only be
achieved through public private partnership.
• Community based and patient centered palliative care services may help to reduce
demand supply gaps in under developed and developing countries.
• Ethical challenges in palliative care can be managed with effective communication and
efficient symptom management.
• Integration of palliative care teaching and training in the undergraduate and
postgraduate medical curriculum is the need of the hour for spread of the concept of
palliative care for all.
• Specialized palliative care service is needed to be developed in India and political will,
government commitment with active participation of society is required to develop self
sustainable model of palliative care at primary health care level.
REFERENCES
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4. Saunders C. The management of patients in the terminal stage. In: Raven R. (Ed).
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6. Radbruch L, Payne S, Bercovitch M, et al. White Paper on standards and norms for
hospice and palliative care in Europe: part 1. European Journal of Palliative Care. 2009;
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7. Sepúlveda C, Marlin A, Yoshida T, et al. Palliative care: the World Health Organization’s
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15. Rajagopal MR, Joranson DE. India: opioid availability – an update. J Pain Symptom
Manage. 2007;33(5):615-22.
16. Duthey B, Scholten W. Adequacy of opioid analgesic consumption at country, global,
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2015;21:95-104.
CHAPTER 20
Update on Anesthesia for
Ophthalmic Surgery
Renu Sinha
INTRODUCTION
In recent years, there are multiple advancements in anesthesia for ophthalmic
procedures for children as well as for adults. Aim of the advancements is to
provide safer anesthesia with better satisfaction to patient as well as to surgeon in
terms of pain relief, surgical conditions and patient’s comfort. Newer drugs and
techniques have been developed to administer safe anesthesia. In last 5–6 years,
due to improved care, preterm babies are routinely coming for various ophthalmic
procedures. On the other hand, due to increase in life-expectancy, more and more
elderly patients are coming with comorbidities for ophthalmic procedures. This
chapter will focus on the recent advances in the field of ophthalmic anesthesia.
RETINOPATHY OF PREMATURITY
Retinopathy of prematurity (ROP) is one of the major causes of preventable visual
impairment worldwide after preterm birth.1 Incidence of ROP is increasing day
by day due to improved survival rate of the preterm babies with improvement of
neonatal intensive care (NICU) facilities. Babies born before 32 weeks of gestation
or weighing less than 1.5 kg and with comorbidities are prone for ROP.2 ROP leads
to vision impairment due to development of abnormal retinal vasculature at the
boundary of vascularized and avascular peripheral retina.2
The multisystemic perioperative concerns in preterm infants include
cardiorespiratory, central nervous system, renal, glucose hemostasis and
temperature management.3 Preanesthetic checkup should include detailed
history of NICU course including apnea, ventilation, cardiorespiratory disease,
intraventricular hemorrhage and relevant examination including airway and
murmur. The investigations include hemoglobin, past chest radiograph, screening
echocardiogram and other investigations according to associated illness. Parents
should be counseled for the possibility of postoperative ventilation in the NICU.
Nil per oral for 4 hours (breast milk) and 6 hours (formula-fed infants) should be
documented.
Anesthesia/Sedation for Laser Therapy

Laser ablation can be done either in the operation theater (OT) or in the NICU as
shifting babies from NICU to OT can be associated with extubation, desaturation
or cardiovascular events. Dilatation of pupil with 2.5% phenylephrine may lead
to pulmonary edema in these children. There should be no movement of head

or eye movements to prevent misdirection of laser application on the normal
retina and therefore these children require sedation or general anesthesia to
complete the procedure.4 Anesthesia/sedation practice for laser therapy varies
from general anesthesia with endotracheal tube (ETT) or laryngeal mask airway
(LMA) and controlled ventilation, topical anesthesia combined with oral or
rectal sedation with chloral hydrate and/or paracetamol, intravenous ketamine
combined with topical anesthesia, remifentanil infusion, morphine infusion and
sub-Tenon’s block.5
Haigh et al.6 reported more frequent adverse cardiac and respiratory events in
children who underwent cryotherapy under topical anesthesia, than who received
general anesthesia and fentanyl analgesia. Eipe N et al.4 reported anesthetic
management and postoperative coarse of twins for laser procedure. Infant with
ETT and controlled ventilation had relatively stable course, in comparison to
other twin with sedation and topical anesthesia. Sub-tenon’s anesthesia with
oral/rectal sedation can be performed in NICU and also avoids intravenous
sedation and intubation. One should select anesthetic or sedation technique
depending on requirement of mechanical ventilation, continuous positive airway
pressure (CPAP) or higher FiO2 and episodes of desaturation or bradycardia.7
Topical proparacaine reduces pain significantly in preterm neonates during
speculum insertion.8 Oral sucrose with or without non-nutritive sucking has
been used for pain relief.9 During laser therapy, all team members should
wear protective goggles. Intravitreal injection of bevacizumab has been used
as an alternative to laser photocoagulation. To prevent movement of baby and
inappropriate injection, sevoflurane has been used as a sole agent for induction
and maintenance of anesthesia without any major complications.10
Anesthetic Management During ROP Surgery

An experienced team of pediatric anesthesiologist, surgeon and trained assistant
with preparation of OT, equipment and monitoring are essential for better
outcome. Reports of anesthetic management for ROP surgery are limited.11,12
Aoyama K et al.12 administered mean dose of 4.6 µg/kg fentanyl for vitrectomy
in preterm infants. In this study, 6 out of 29 infants required postoperative
ventilation for more than 2 days. Drugs with very short duration of action like
remifentanil may reduce the apnea incidence after ROP surgery.
Sinha R et al.13 administered peribulbar block in 24 preterm infants who
underwent viteroretinal surgery for ROP. None of the infant had postoperarive
apnea or bradycardia, it can be attributed to opioid and muscle relaxant sparing
effects of peribulbar block.
Postoperative Care
Babies are monitored either in NICU or in PICU depending on the gestational age,
risk of postoperative apnea and need for postoperative ventilation. Monitoring
includes SpO2, ECG, NIBP and respiration with alarm for apnea. Sinha R et al.11
studied postoperative course of preterm babies who underwent ROP surgery and
concluded that more than 42 weeks post gestational age babies who did not have
any comorbidity can be managed in properly equipped postanesthesia care unit
(PACU).
Update on Anesthesia for Ophthalmic Surgery 233
ULTRASOUND-GUIDED OPHTHALMIC BLOCKS

In recent years, ultrasound has been widely used for peripheral nerve block with
the advantage of increased safety, need for lesser volume of local anesthetic drugs
and real time visualization of local anesthetic spread.14 In adults, most of the
eye surgeries are performed under ophthalmic blocks. These are usually needle
blocks like retrobulbar block, peribulbar block and sub-Tenon’s block. These
blocks are being performed blindly and may lead to various complications, i.e.
retrobulbar hemorrhage, globe perforation, optic nerve damage, spread of drug
into muscles and in the central nervous system.15
Ultrasound will help in guiding the needle trajectory and spread of local
anesthetic. It improves the quality and safety of ophthalmic block. A preblock
scan of the globe and adnexa is always useful especially in myopic eye to rule
out staphyloma and to evaluate the axial length. Monitoring of needle path with
ultrasound may prevent globe perforation with needle blocks. B-mode ultrasound
is used for USG-guided block.14
Najman et al.16 studied periconal blockade with or without ultrasound
guidance. They used B-scan liner array transducer at 12 MHz with a circular
footprint, which was placed at supraorbital rim and focused at 6 cm. Longitudinal
and axial approaches were used for globe imaging and to obtain axial length
respectively. They used 25 mm long 23 G needle, which was attached to an
extension to inject the drug (6 mL of 0.75% levobupivacaine). They found that
USG did not reduce the complications, however it reduced the rate of intraconal
needle tip placement along with reduction of needle length insertion into the
orbit. They concluded that USG-guided block is safer, as it will reduce chances of
globe perforation especially in high myopic eyes.
Luyet C et al.15 studied real time visualization of ultrasound guided
retrobulbar block in cadavers. They used a 22 G short needle and small curved
array transducer. Long axis approach was used and needle was introduced till
the needle tip was 2 mm away from the optic nerve. Spread of the 2 mL dye was
documented by CT scan into the muscle cone and behind the posterior sclera.
USG guided technique improved the safety and efficacy of block due to needle
visualization and reduction of local anesthetic amount.
Calenda E et al.17 compared diffusion of local anesthetic after peribulbar
and sub-Tenon’s block by ultrasound with 12 Hertz linear probe. In sub-Tenon’s
group, spread of local anesthetic solution was on both sides of optic nerve into
the sub-Tenon’s space with a characteristic T-sign. In the peribulbar group, local
anesthetic solution spreads in the peribulbar, retrobulbar and sub-Tenon’s space
with similar T-sign.
There are many concerns regarding the safety of the use of ultrasonic energy
to the eye while performing ultrasound for ophthalmic block. Recommendations
from Food and Drug Administration (FDA) and World Federation for Ultrasound
in Medicine and Biology have imposed that for using ultrasound around the eye,
i.e. mechanical index (an estimate of the potential to produce macrostreaming
and cavitation) and thermal index (a ratio relating power output to the ability to
raise tissue temperature by 1° C) should be reduced from 6.0 and 1.9–0.23 and <1,
respectively. So normal transducer used for peripheral nerve blocks may not be
suitable for ophthalmic blocks. Specific orbital-rated transducer with decreased
mechanical and thermal index should be used as nonorbital-rated transducers
leads to mechanical and thermal changes in the eye.18 Even after establishing
safety norms, a device should not be in contact with eye for more than 90 seconds
continuously. Other drawbacks of ultrasound are requirement of more time for
performing the block, discomfort to the patient due to pressure of the transducer
on the eye, need for assistant to inject the drug or to hold the transducer and
difficulty in recognizing the finer needle.14 Ultrasound-guided ophthalmic blocks
may take more time to perform, however, safety provided with this technique
should not be compared with time or need for assistance during ophthalmic
blocks.
SUB-TENON’S BLOCK
Sub-Tenon’s block was first described in 1884 by Turnbull and reintroduced in
1990. Peribulbar or retrobulbar anesthesia has been associated with numerous
ocular complications including diplopia, orbital hemorrhage, globe perforation,
central retinal vein or artery occlusion, brainstem anesthesia, optic nerve trauma
and ptosis. Many patients experienced pain of needle injection and intravenous
sedation during injection.19 Roman et al.19 evaluated efficiency and safety of
sub-Tenon’s block and found it safe and efficient anesthetic technique for anterior
as well as posterior segment surgery. They concluded that sub-Tenon’s block is a
good alternative to peribulbar block.
Topical anesthesia has been widely used for cataract surgery in adults.
Ruschen et al.20 compared patient satisfaction with sub-Tenon’s block and
topical anesthesia for cataract surgery and concluded that sub-Tenon’s block
provides significantly higher satisfaction scores than topical anesthesia alone.
Local anesthetic is deposited into the sub-Tenon’s space, which blocks the short
ciliary nerves. Akinesia occurs due to direct blockade of the anterior motor fibers
when they enter into the extraocular muscles. Local anesthetic surrounds the
optic nerve and diffuses into the retrobulbar space thus affecting he vision of the
patient.21
Sub-Tenon’s Block Technique

Any of four quadrants can be used for the sub-Tenon’s block. But inferonasal
quadrant, which is most commonly used as distribution of drug, is better and
it avoids surgical area and damage of vortex veins. Many types of long and short
cannulas (metal, silicon, plastic) are available for the block but a metal, 19 G, 2.54
cm long curved and blunt cannula is most commonly used.
Topical anesthetic agent is instilled into the operating eye for anesthesia.
Povidone iodine 5% is instilled for sterility. The eye is draped and patient is asked
to look upward and outward to expose inferonasal quadrant. At 5–7 mm away
from limbus, conjunctiva and Tenon’s capsule are gripped with non-toothed
forceps. With the help of scissors, a small incision is made to expose white sclera.
Sub-Tenon’s cannula attached to the syringe filled with local anesthetic solution
is inserted. Cannula follows the curvature of the globe and drug is injected after
negative aspiration. Volume of drug varies from 1.5 mL to 11 mL. About 3–5 mL
drug is administered for anterior segment surgery and 7–10 mL drug is injected
for posterior segment surgery. Trabeculectomy and strabismus surgery can also
be performed with sub-Tenon’s block.21
Metal cannula used for sub-Tenon’s block is not freely available. A 20 G plastic
intravenous cannula can also be used through sub-Tenon’s route, it provides
similar operating conditions, akinesia and analgesia like metal cannula.22 The
sub-Tenon’s block can also lead to minor complications like pain on injection,
chemosis, subconjunctival hemorrhage or leakage of drug. Major complications
associated with the block include orbital and retrobulbar hemorrhage, rectus
muscle paresis and trauma, globe perforation, the central spread of local
anesthetic and orbital cellulitis.
Application of Honan balloon at 30 mm Hg for 10 minutes after sub-Tenon’s
block reduces IOP significantly without improving the quality of anesthesia.
Addition of 15–30 IU/mL hyaluronidase with local anesthetic may improve the
quality of motor blockade. However, cataract surgery can be performed without
hyaluronidase with similar patient comfort and surgeon satisfaction.
Huang P et al.23 compared postoperative redness of the eyes after sub-Tenon’s
block and topical anesthesia following cataract surgery. They found only 57.2% of
eyes were red due to minor subconjunctival hemorrhage following sub-Tenon’s
block on the first postoperative day. They suggested that due to mild redness,
sub-Tenon’s block should not be deferred considering its benefit.
Kumar N et al.24 studied frequency of hemorrhagic complications with
sub-Tenon’s block in patients on aspirin, warfarin or clopidogrel having elective
cataract surgery. These patients had minor subconjunctival hemorrhages, which
were more than in the control group. However, there were no sight-threatening
hemorrhagic complications. They concluded that anticoagulants may be safely
continued in patients for phacoemulsification under sub-Tenon’s block.
Sub-Tenon’s block has been used in children undergoing strabismus surgery,
vitreoretinal surgery and cataract surgery under general anesthesia. Chhabra A
et al. and Calenda E et al. studied effects of sub-Tenon’s block in vitreoretinal
surgery and concluded that it provides effective intraoperative analgesia and
reduces postoperative analgesic requirement.25,26
Tuzcu K et al.27 found that sub-Tenon’s block is not effective in reduction of
oculocardiac reflex (OCR) and postoperative nausea and vomiting (PONV) after
strabismus surgery in children. In contrast, Ramachandran R et al.28 concluded
that sub-Tenon’s block significantly decreases incidence of intraoperative OCR
and PONV but does not provide superior postoperative analgesia in comparison
to intravenous fentanyl in pediatric strabismus surgery.
In conclusion, sub-Tenon’s block is safer than other needle blocks and
provides equally effective analgesia and akinesia with lesser volume of local
anesthetic drug. It can be administered in patients on anticoagulants without
major hemorrhagic complications and can be safely administered in children
under general anesthesia.
SEDATION DURING OPHTHALMIC PROCEDURES

Sedation is required during surgery under topical or regional anesthesia to allay
anxiety and to enhance patient cooperation during surgery. Till date no ideal
drug is available for sedation. In ophthalmic surgery, propofol, midazolam and
propofol-ketamine combination has been used frequently for sedation. Recently
dexmedetomidine has been used for sedation during ophthalmic surgery under
regional anesthesia.
Erdurmus M et al.29 studied effect of dexmedetomidine sedation during

cataract surgery under topical anesthesia and found it safe. Patient and surgeon
satisfaction were improved with decrease in surgical pain. Dexmedetomidine
provides satisfactory sedation with stable hemodynamics and decrease in IOP
under local anesthesia for cataract surgery.
Dexmedetomidine may be a preferred agent in patients with open eye
injuries. When used as premedication at 0.4 µg/kg bolus dose decreases IOP
and reduces pressor response of intubation till 5 minutes after laryngoscopy.30
Dexmedetomidine administration before induction prevents increase in IOP
following suxamethonium and intubation.
The effect of intravenous dexmedetomidine 0.5 µg/kg premedication was
compared with 2 µg/kg clonidine and normal saline on IOP after suxamethonium
administration and intubation.31 Dexmedetomidine was found to be better in
blunting the IOP than clonidine and may be useful in penetrating eye injury
cases. Dexmedetomidine (0.5 µg/kg) sedation was also compared with ketofol
during cataract surgery. It was noticed that though, both drugs provided similar
sedation, ketofol has advantage of rapid onset and shorter recovery without
adverse effects on respiration.32
During vitreoretinal surgery under regional anesthesia, 0.25 µg/kg loading
dose with 0.25–0.4 µg/kg maintenance dose of dexmedetomidine was found to
be better than 0.5 µg/kg loading dose and midazolam-fentanyl combination in
terms of level of sedation, hemodynamics, respiration and surgeon satisfaction
without PONV.33 In comparison to propofol, dexmedetomidine in vitreoretinal
surgery under sub-Tenon’s block maintained better respiratory function,
analgesia and patient’s satisfaction however hemodynamics, discharge time and
surgeon satisfaction were similar.34
Dexmedetomidine has been found to increase motor as well as sensory block
duration with decreased need for postoperative analgesic and good quality sleep
when used as an additive with 0.75% levobupivacaine for sub-Tenon’s block at a
dose of 20 µg/kg in vitreoretinal surgery.35
In children, dexmedetomidine (0.5 µg/kg and 1.0 µg/kg) has been used
with ropivacaine for retrobulbar block in vitreoretinal surgery. It was found
that dexmedetomidine reduces minimum local anesthetic concentration of
ropivacaine, with reduction in postoperative analgesic requirement without
causing any neurological side effects.36 In children, intravenous dexmedetomidine
at 0.2 µg/kg/h with 1 µg/kg fentanyl was found to decrease emergence agitation,
fentanyl rescue need following desflurane anesthesia in strabismus surgery.37
Lili X et al.38 found that 0.5 µg/kg IV dexmedetomidine with sevoflurane and
remifentanil in children undergoing vitreoretinal surgery leads to reduction in
emergence agitation with attenuation of extubation response.
ANTIPLATELET AND ANTICOAGULANT THERAPY AND

OPHTHALMIC ANESTHESIA
Elderly patients coming for ophthalmic surgery may have comorbidities and may
be receiving anticoagulant therapy (ACT) or antiplatelet therapy (APT) to prevent
thromboembolic events. There is always a risk of thromboembolic event on
discontinuation of these drugs. On the other hand, there is also risk of bleeding
during regional ophthalmic blocks and surgery with continuation of these drugs.
Newer antiplatelet and anticoagulant have different pharmacodynamics and

pharmacokinetics. So, the effects of these drugs on regional ophthalmic blocks and
surgery will be different with different risk for bleeding. Antiplatelet drugs include
aspirin and thienopyridines derivatives. Thienopyridine derivative include
clopidogrel, ticlopidine and newer prasugrel, ticagrelor. Platelet dysfunction
persists from 5 to 7 days after stopping the clopidogrel and 10–14 days after
ticlopidine. Peak plasma level of ticagrelor reaches within 1.5 hours Glycoprotein
IIb/IIIa receptor antagonist includes eptifibatide, abciximab and tirofiban. After
stopping these drugs, platelet function are impaired till 8–48 hours.14
Anticoagulant drugs include warfarin, heparin (unfractionated, fractionated
low molecular weight). Fondaparinux plasma half-life is 21 hours after once daily
dose. Newer anticoagulants include dabigatran, rivaroxaban and apixaban. Half-
life of dabigatran after a single dose is 8 hours and after multiple dose 17 hours.
Rivaroxaban has rapid onset of action and peak plasma level comes in 3–4 hours.
Apixaban is absorbed rapidly and peak plasma level reaches within 2 hours.
Surgeon and anesthesiologist should decide regarding continuation or
stopping these drugs for ophthalmic blocks and surgery on individual case
basis after consulting the treating cardiologist and patient with the discussion
of risk of a thromboembolic event versus. the risk of poorly controlled bleeding.
If patient is having high risk of thromboembolic event such as recent stent
insertion then antiplatelet should be continued. Recent data suggest that for most
of the ophthalmic surgeries, ACT/APT can be continued without major sight
threatening complications.39
It has been studied that there is significant increase in minor complications
with needle block as well as sub-Tenon’s block with continuation of ACT/APT
for cataract surgery. However, there was no sight threatening complications.40
Authors reported that needle regional block can be performed safely for anterior
segment and vitreoretinal surgery with ACT/APT.41
Phacoemulsification cataract surgery can be safely performed in
uncomplicated cataract without stopping the ACT/APT with topical anesthesia.42
Though incidence of subconjuctival hemorrhage is more in patients with ACT/
APT, intraoperative and postoperative complications and visual gain is not
affected.
Gallice M et al.43 noticed that in vitreoretinal surgery, if INR is less than 3 in
patients on ACT, perioperative risk of ocular bleeding is not increased. Ryan A et
al.44 found mild hemorrhagic oozing during vitrectomy and dispersed bleeding
in vitreous cavity postoperatively with continuation of APT or ACT. Passemard
M et al.41 found that sight threatening hemorrhagic complications were more in
patients on APT than patients on ACT after VR surgery. In contrast, Oh J et al.45
found that use of anticoagulant was associated with a higher risk of postoperative
intraocular bleeding without serious consequences. Risk of sub-retinal
hemorrhage is also more with continuation of ACT/APT in age-related macular
degeneration.46 Malik AI et al.47 concluded that transconjuctival sutureless
vitrectomy under subconjuctival anesthesia may be safer in patients on ACT/
APT. Fabinyi DC.48 studied post-vitrectomy hemorrhage in diabetic eye with ACT/
APT and found that continuation of ACT/APT perioperatively lead to increase
in the risk of postoperative vitreous cavity hemorrhage needing resurgery in few
patients. They suggested preoperative discontinuation of ACT/APT might lead to

decrease in risk of postoperative bleeding in diabetic retinopathy.
In trabeculectomy, aspirin can be continued safely but warfarin increases the
risk of serious bleeding with risk of failure of surgery. Even with aspirin, risk of
hyphema is increased after surgery but it does not affect surgical outcome.49 Law
SK et al.50 compared hemorrhagic complications in patients who are on ACT/
APT in glaucoma surgery and suggested that chronic ACT/APT use is associated
with increase in hemorrhagic complications in glaucoma surgery.
In oculoplastic surgery, continuation of ACT/APT is associated with serious
hemorrhagic complications prolonging surgery, however incidence is low.
Therefore, decision should be taken judiciously weighing sight threatening
complications with life-threatening complications.51
CONCLUSION
To conclude, ROP surgery should be performed in a multispecialty hospital with
NICU facility and trained staff. Ultrasound is good for screening the orbit for any
abnormality, i.e. staphyloma. Ultrasound guided block can prevent complications
and decrease the drug dose. Sub-Tenon’s block is a safe block and provide similar
akinesia and anesthesia in comparison to peribulbar block. Dexmedetomidine
helps in preventing the rise in IOP following suxamethonium and intubation. It
prevents emergence delirium in children. ACT/APT can be continued safely in
most of the ophthalmic procedures except trabeculectomy and major oculoplasty
surgery.
KEY POINTS
• P remature babies presenting for surgery of retinopathy of prematurity (ROP), preterm
babies are at prone for postoperative apnea, bradycardia and require NICU with
ventilation facility.
• Ultrasound helps in guiding the needle trajectory and improves the quality and safety
of ophthalmic block.
• Preblock scan of the globe and adnexa with ultrasound is useful especially in myopic
eye to rule out staphyloma and to evaluate the axial length.
• Specific orbital–rated transducer with decreased mechanical and thermal index (0.23
and <1) should be used as nonorbital-rated transducers leads to mechanical and
thermal changes in the eye.
• Sub-Tenon’s block causes minimal increase in IOP, provides effective analgesia as well
as akinesia and requires lesser volume of local anesthetic drug in comparison to other
needle block. It can be administered in patients on anticoagulants without major
hemorrhagic complications.
• Dexmedetomidine is an alternative for sedation during ophthalmic surgery. It decreases
IOP and blunts the intubation response, so can be used in open eye injuries.
• Discontinuation of anticoagulants and antiplatelet medication should be weighed
in terms of vision threatening versus life-threatening complications. Oculoplasty
and glaucoma surgery and vitreoretinal surgery are more prone for hemorrhagic
complications with continuation of these drugs.
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CHAPTER 21
Perioperative Neurological Complications
Kirti N Saxena
INTRODUCTION
Anesthesia and surgery are associated with many complications. Many of the
complications which occur in the operation theater may not be obvious to
the patient postoperatively. The importance of neurological complications is
that though they are rare, they may be temporary or may persist for prolonged
period of time resulting in permanent debility which may be life changing for the
patients. They are very distressing to patients and their relatives and may also
result in litigation. The overall incidence of neurological complications is not
available but incidence of specific injuries exists.
Both surgery and anesthesia are associated with neurological complications.
Neurological complications may occur following surgery because of direct nerve
injury whereas anesthetic complications may occur for a variety of reasons.
Neurological complications are seen with general anesthesia as well as with
regional anesthesia. Direct nerve injury, ischemic neurological injury and toxic
effects of drugs, all contribute to neurological complications. Recently a lot of
attention has been focused on effect of anesthetic agents on the neurological
impairment of the developing brain. In this review we shall highlight the various
neurological complications associated with anesthesia.
Broadly the perioperative neurological complications can be divided into
systemic complications and regional complications. Systemic complications are
generally seen following general anesthesia but are sometimes seen following
regional anesthesia also. The mechanism of systemic neurological complications
is not very clear but there is evidence from animal studies which supports
certain processes occurring at the level of the central nervous system. Since
anesthetic agents depress consciousness, they produce central suppression of
neurological conduction. Anesthetic induced neurodegeneration may occur due
to suppression of synaptic signaling. The exact molecular mechanism of action
of anesthetics on suppression synaptic signaling is unclear and probably works
through NMDA receptors and GABA receptors.1
POSTOPERATIVE DELIRIUM
Delirium is defined as a depression of the level of consciousness which may be
associated with disturbance of attention which occurs over a short period of
time. It is more common in the postoperative period in the elderly but is also
Perioperative Neurological Complications 243
seen in children. The diagnosis is made by doing preoperative evaluation of the

conscious level and detecting any postoperative change that may occur. It is
common following cardiac surgery. A recent study has shown its incidence to
be 45% of all elderly patients undergoing general anesthesia. It results in delay
in discharge from hospital.2 The factors associated with postoperative delirium
have been identified as: pre-existing cognitive disorders or brain damage,
age over 65 years, renal failure, anemia, drug addiction, use of concomitant
medications (narcotics and high doses of corticosteroids), intraoperative
hypoxia, acidosis or hypoventilation, postoperative electrolyte disturbances,
fever and sepsis. Coronary artery bypass surgery is associated with high risk of
postoperative delirium. Use of anticholinergic premedication such as atropine
has been associated with the central anticholinergic syndrome which presents
as postoperative delirium.3 Presence of pain has also been found to contribute
to delirium in the hospital setting.4 Also, evidence suggests that maintaining
adequate depth of anesthesia reduces the incidence of delirium in elderly
patients in the postoperative period.5
Prevention of postoperative delirium is difficult as several pathological
pathways have been implicated leading to its occurrence such as imbalance
of neurotransmitters, neuroinflammation, dysfunction of the endothelium,
impaired oxidative metabolism and altered availability of large neutral amino
acids. Preference for regional anesthesia has been shown to prevent delirium
provided deep sedation is not used with it. Use of antipsychotic medication has
not been shown to consistently improve the situation in postoperative delirium
and is therefore not recommended. Treatment of precipitating causes such
as renal impairment, electrolyte and acid-base imbalances should be done for
alleviation of the condition.6 Sensory enhancement, mobility enhancement and
methods to improve cognition and restoration of the diurnal rhythm, all help in
alleviation of the condition.3
POSTOPERATIVE COGNITIVE DYSFUNCTION

Postoperative cognitive dysfunction (POCD) is increasingly recognized as a
complication of major surgery and results in impaired daily activity and increased
morbidity and mortality. It is still not clear at what point of time cognitive function
returns after recovery from anesthesia. POCD may be short-term or it may persist
for significant time postoperatively. The time of recovery of cognitive function is
not the same for all patients and is dependent upon the type of anesthetic drugs
used, type of surgery and several patient related factors. Neurotoxicity of general
anesthetic drugs has been proposed as a cause but not conclusively proven. Drugs
such as barbiturates and benzodiazepines have been associated with POCD.
Intraoperative events such as air embolism, thromboembolism or microemboli
seen during orthopedic surgeries can also cause POCD. 6 It has also been found
that among the volatile anesthetics, isoflurane causes higher incidence of POCD
than desflurane. It has been shown to increase the levels of interleukin-6 resulting
in anesthetic induced neuroinflammation.7
The POCD has a definite correlation with old age. Improvement of
general health following surgery which results in decreased pain, decreased
inflammation, increased cerebral blood flow, and enhanced daily functional
ability have been shown to enhance the cognitive function of patients. Factors
such as presence of pain, sleep deprivation, isolation, hypoxemia, inflammation,

electrolyte disturbances and hypothermia contribute to development of short-
term POCD.8 Cardiac surgery with cardiopulmonary bypass (CPB) is known
to increase the occurrence of long-term POCD, and reducing the period of
CPB has been shown to reduce its occurrence. It has been suggested that CPB
results in lodging of cerebral microemboli in the brain which result in various
types of neurological impairments including POCD. Other intraoperative factors
which may contribute to POCD are: hyperglycemia, use of bubble oxygenator,
normothermic perfusion and not using neuroprotective drugs perioperatively.6
Development of postoperative delirium following cardiac surgery is associated
with risk of development of POCD and long-term cognitive impairment.9
POSTOPERATIVE VISUAL LOSS

Postoperative visual loss (POVL) is a rare complication having grave implications.
It presents as complete loss of vision in one or both eyes and rarely as partial
loss of vision which is painless and presents after the patient has recovered fully
from anesthesia. It is most commonly seen after spine surgery, cardiac surgery,
head and neck surgery and rarely after urological surgery, nasal sinus surgery
and gynecological procedures. The cause of POVL is anterior ischemic optic
neuropathy (AION) and posterior ischemic optic neuropathy (PION), cortical
blindness, corneal damage, ischemia of the central retinal artery or a branch
of this artery, posterior reversible encephalopathy syndrome and rarely acute
glaucoma.10
The cause of ischemia may vary with the type of surgery. AION is usually
associated with cardiac surgery whereas PION is associated with spine surgery
and neck dissection. Since POVL has been found to have the highest association
with spine surgery most of the literature is focused around it. Spine surgery is
usually carried out in the prone position and there may be direct pressure on
the eyes due to improper positioning. Increased intra-abdominal pressure and
intrathoracic pressure results in, raised intraocular pressure leading to ischemic
optic neuropathy (ION) and retinal artery occlusion. Other contributing factors
are: use of Wilson frame, prolonged surgery, high amount of blood loss and late
and inadequate replacement of intravascular volume with colloids.11 Retinal
examination reveals a normal fundus immediately after surgery and signs of
optic atrophy appear after 4–6 weeks. Magnetic resonance imaging (MRI) should
be done to rule out intracranial pathologies such as stroke.12 There is no specific
treatment for POVL and conservative management has to be done. There is no
role for antiplatelet agents, steroids, or intraocular pressure-lowering agents in the
treatment of perioperative ION. Since prognosis is poor some preventive measures
have been advocated. The ASA task force on POVL recommended that blood
pressure should be maintained within 24% of baseline mean arterial pressure or
with a minimum systolic blood pressure of 84 mm Hg. Central venous pressure
should be maintained and colloids should be used along with crystalloids to
replace blood loss. The intraoperative hematocrit should be checked periodically
and should be maintained around 28% (range 18–37%). There appears to be
insufficient evidence for advice regarding use of vasoconstrictors and decision
about their use should be decided on a case to case basis. Direct pressure on the
eyes must definitely be avoided. In high-risk patients it has been advocated that
the patient’s head should be positioned level at or higher than the level of the
heart. Spine procedures should preferably be done in stages.13
Central and branch retinal artery occlusion may be seen following cardiac
surgery. The cause is usually air embolism when patient is on cardiopulmonary
bypass with bubble oxygenators and thromboembolism is causative in other
types of cardiac surgery. Emboli can fully or partially cut off the blood supply
of the retinal artery or its branch. Paradoxical embolism may also be seen in
patients with cardiac shunts. POVL has also been seen following neck dissection
with ligation of internal jugular vein resulting in high intraocular pressure.14
Bilateral infarctions of the posterior cerebral arteries and occipital lobes leading
to POVL has been ascribed to thromboembolism of the retinal artery following
decompression of the spine for a metastatic adenocarincoma.15 There are
other reported causes of POVL after varying surgeries. POVL has been reported
following cesarean section under spinal anesthesia in a 20 years old patient. The
cause was ascribed to similar factors as spine surgery that is, severe anemia,
massive blood loss and use of crystalloids.16 Raised intra-abdominal pressure
has been associated with hemorrhage leading to cortical blindness following
laparoscopic surgery.17,18 Other causes of cortical blindness are postoperative
posterior reversible encephalopathy syndrome19 and Purtscher’s retinopathy.20
These cases require neurological consultation for diagnosis and management.
SPINAL CORD ISCHEMIA

Paraplegia is a devastating complication of aortic surgery. It is usually seen
following surgery for aortic aneurysms and thoracic endovascular aortic repairs
(TEVAR). The extent of neurological deficit can range from mild paraparesis to
flaccid paraplegia. Prognosis of paraplegia is very poor and recovery is slow. The
unique blood supply of the spinal cord is a contributing factor in the development
of spinal cord ischemia (SCI). The spinal cord receives its blood supply from
the anterior spinal artery and the radicular arteries. Ligation of collateral artery
during surgical dissection, application of aortic cross-clamp and coverage of a
collateral artery by an endovascular stent can cause immediate interruption
of blood flow through the intercostal arteries resulting in SCI. Postoperative
collateral thrombosis or a decrease in spinal cord perfusion pressure due to
factors such as hypotension, increased cerebrospinal fluid (CSF) pressure of
ischemia–reperfusion can result in delayed-onset SCI.8
There are several factors which contribute to SCI following TEVAR but the
pathophysiology is not very clear. The spinal cord is very prone to hypoperfusion.
Using multiple stent grafts in long segments of the thoracic aorta can reduce
perfusion of intercostal (T7-L1) and lumbar segmental arteries which supply
the anterior spinal artery resulting in ischemia of the spinal cord. Peroperative
hypotension is an important contributing factor.21 Recommended monitoring
includes use of transesophageal echocardiography during endovascular thoracic
aorta procedures to detect endovascular graft leak and motor or somatosensory
evoked potentials to guide therapy. Techniques for prevention are: cerebrospinal
fluid drainage to prevent spinal cord damage, moderate hypothermia and
optimization of spinal cord perfusion pressure.22 Apart from aortic surgery,
SCI has also been reported after abdominal surgery for hepatic subcapsular
hematoma followed by abdominal packing.23
STROKE
Perioperative stroke can be a catastrophic event not only for the patient but also
the caregiver. It is defined as any acute ischemic or hemorrhagic cerebrovascular
event lasting for at least 24 hours and occurring intraoperatively or within 30 days
following surgery.
The risk of perioperative stroke is higher after cardiac surgery but it has
been seen after noncardiac, nonvascular and non-neurosurgical patients as
well, though the incidence is lower. There are several predisposing factors for
perioperative stroke and these include: older age, coexisting renal disease,
myocardial infarction in the previous six months, atrial fibrillation, valvular
heart disease, severe chronic obstructive lung disease, congestive heart failure,
hypertension, carotid artery disease, tobacco abuse, history of transient ischemic
attack and previous history of stroke.24 The etiology of perioperative stroke can vary
from cardioembolism leading to ischemic stroke. Paradoxical embolism may be
seen in patients with left to right intracardiac shunts. Cerebral thromboembolism
or hypoperfusion may occur in patients with atherosclerotic cerebral vessel
plaques. In patients with hypercoagulable states cerebral sinus or cortical vein
thrombosis can result in venous infarction leading to stroke. Hemorrhagic stroke
may occur in hypertensive patients or those on anticoagulants. Fat embolism
and air embolism may occur in certain types of surgeries such as long bone
surgery and neck dissection resulting in stroke. The 30 day mortality following
stroke is increased eight fold.25 Preoperative hemiplegia is a sign of the severity
of a previous stroke and impaired cerebral circulation and is a strong prognostic
indicator for peroperative stroke in patients undergoing vascular surgery. The
incidence of stroke is high in the postoperative period with most strokes occurring
after the first 2 days of surgery.26
So, what is the sequence of events leading to a stroke? Postoperative
endothelial dysfunction and inflammation associated with release of nitric
oxide, prostacyclin, and other endothelial-derived factors lead to thrombosis,
vasospasm and plaque rupture. The stress of surgery adds to the hypercoagulable
state and withholding anticoagulant and antiplatelet agents in the perioperative
period may further add to the prothrombotic state. Apart from cardiac surgery
and carotid endarterectomy, certain types of noncardiac and non-neurological
surgery are associated with a higher incidence of stroke. These are: peripheral
vascular surgery, hip arthroplasty, neck dissection for malignancy and shoulder
surgery in the beach chair position. Intracranial bleed may also occur during
endoscopic nasal procedures manifesting as stroke.27
Minor strokes or transient ischemic attacks or covert attacks can be easily
missed in the immediate postoperative period. The effects of anesthetic drugs
may persist into the postoperative period and confuse the diagnosis. Further,
a diagnosis of POCD can delay the diagnosis of stroke. There are no chemical
biomarkers of stroke such as troponin T for a myocardial infarction. The
neurovision pilot study emphasized that covert stroke after surgery and anesthesia
is now recognized as a potential cause of poor recovery, POCD, depression,
dementia and ongoing disability. Of the elderly, 11.4% patients undergoing
noncardiac surgery were found to have covert stroke which was detectable only
on MRI.28
Patients with recent stroke have impaired cerebral autoregulation and

chemoregulation. It has been suggested that after recent stroke, elective
surgery should be postponed by 1–3 months to prevent a perioperative stroke.
However, this needs to be reevaluated when the surgery is urgent or the patient
has malignancy. There are no clear guidelines on this and each case should
be decided on its own merit.29 There are currently no guidelines regarding
perioperative management of anticoagulants and antiplatelet agents to prevent
perioperative stroke. Continuing aspirin in the perioperative period has not been
shown to reduce the incidence of stroke. Preoperative atrial fibrillation should
be medically managed and anticoagulant treatment should be substituted
with bridging therapy. Betablocker therapy should continue perioperatively.
Perioperative use of statins reduces thromboembolic phenomenon including
stroke. Use of regional anesthesia for surgeries such as hip arthroplasty also
reduces perioperative stroke. Blood sugar should be controlled between 60 mg%
and 180 mg%. Hypotension must be avoided in susceptible patients and it should
be defined by percentage fall from preoperative blood pressure rather than
absolute values. Induced hypotension in patients undergoing surgery requires
caution and an attempt should be made to correlate cerebral artery pressure with
the measured arm pressure.30
NEUROEXCITATORY PHENOMENON
Several neuroexcitatory phenomenon have been seen with the use of anesthetic
agents. These range from frank convulsions to phenomenon such as myoclonus
and tremors. Epilepsy represents the most severe neuroexcitatory phenomenon.
Seizures are a result of imbalance between excitatory and inhibitory phenomenon.
Perioperative seizures are a cause for concern for both anesthesiologists as
well as surgeons because they may not be detected when the patient is under
anesthesia. There are many predisposing factors which lead to convulsions
occurring for the first time in patients without seizure disorder. These are:
hyponatremia, hypocalcemia and hypoglycemia. Several anesthetic agents have
been associated with proconvulsant properties. These include: induction agents,
local anesthetics, volatile agents, opioids and ketamine.
Enflurane has known epileptogenic properties and its use has been
discontinued. Major epileptoid signs on EEG may be seen in both epileptic
and normal children similar to enflurane. There are case reports of convulsions
with use of sevoflurane.31 The epileptogenic effects of sevoflurane on the brain
are found at concentrations more than 1.5 MAC and with hypocapnia. Use of
8% sevoflurane for induction of anesthesia does not cause clinical seizures but
epileptiform EEG may be seen. These effects are reduced by concomitant use of
nitrous oxide and midazolam.32 Other inhalational agents such as halothane do
not have epileptogenic activity. Isoflurane and desflurane have a protective effect
on the brain and have been used for treatment of refractory status epilepticus.31
Opioids have also been shown to have epileptogenic effects. These effects
are seen with metabolites of morphine and pethidine, i.e. morphine-3-
glucoronide and norpethidine respectively. These respond to benzodiazepine
administration. It has been suggested that neuroexcitatory phenomenon
are mediated by selective stimulation of κ and µ opioid receptors in a dose-
dependent manner and inhibition of pyramidal neurons through reduced
GABAergic interneuronal activity. Also, hyperpolarization activated potassium

currents are inhibited.33 Myoclonic movements and chest wall rigidity are seen
with fentanyl and methadone. Rigidity is typically seen with the use of high-dose
opioids during induction of or emergence from anesthesia the nonparalyzed
patient. Sometimes it may become difficult or impossible to ventilate the patient
when this occurs. This should be treated with administration of nondepolarizing
muscle relaxants.34
All intravenous induction agents have been shown to induce neuroexcitatory
activity such as myoclonus and opisthotonus on induction of anesthesia. These
activities are most commonly seen with etomidate and rarely with barbiturates
and propofol. Convulsions have also been seen with etomidate. At higher doses,
all these agents act as anticonvulsants and are used in management of refractory
seizures. Ketamine, which is an NMDA receptor agonist has similar properties
as other induction agents; at low doses it may cause convulsions whereas higher
doses exhibit anticonvulsant properties.31
Local anesthetics are considered safe when they are used in indicated
doses at the appropriate sites. Systemic neurotoxicity is seen when they are
given in toxic doses or after accidental intravascular administration of clinically
acceptable doses. Neurotoxicity is seen more commonly with lignocaine than
with bupivacaine. Signs of neuroexcitation may precede depression of the
central nervous system in a biphasic manner. The signs and symptoms are:
perioral numbness, light headedness, dizziness, tinnitus and depression of
mental faculties. Shivering, muscle tremors, twitching progressing to tonic-
clonic seizures may be seen. The probable mechanism of these neuroexcitatory
phenomenon is blockade of the inhibitory centers by the local anesthetics
resulting in unopposed activity of the facilitatory centers. These are usually
easily treated with intravenous diazepam or midazolam otherwise thiopentone
can be used. These neuroexcitatory phenomena may be followed by coma and
respiratory depression if timely treatment is not given.35
COMPLICATIONS OF NEURAXIAL ANESTHESIA

Although neurological complications of neuraxial blockade are very rare they
can have catastrophic consequences such as paraplegia for the patient. These
may be a result of complications such as epidural abscess, epidural hematoma,
spinal hematoma or direct injury to the spinal cord. The risk of hematoma is
more common with epidural anesthesia with catheter placement which may be
complicated by coagulation disorders or anticoagulant treatment. It presents
with symptoms of acute spinal cord compression. There may be pain, numbness,
motor weakness and bladder and bowel involvement. The diagnosis is made by
CT scan or MRI. It requires urgent surgical intervention for evacuation to reverse
the neurological damage.36 However, in a patient on anticoagulants spontaneous
recovery was seen following conservative managent.37
Epidural abscess is another dreaded complication of epidural anesthesia. It
has similar presentation as epidural hematoma but has a delayed manifestation
accompanied by fever. It is accompanied by raised total blood leukocytic
count, increased cerebrospinal fluid proteins and presence of leukocytes in the
cerebrospinal fluid. Diagnosis is by imaging and treatment is surgical drainage of
abscess and administration of appropriate antibiotics for 4–6 weeks.38
Direct trauma to the spinal cord by a spinal needle or catheter can result in
cauda equina syndrome. This syndrome presents as bladder atony, loss of control
of micturition, and injury of the lower motor neuron including paraplegia.39 It
has also been seen following exposure of the spine to very large doses of local
anesthetics and following infection and spinal hematoma leading to compression
of the cord. It is recommended that mean blood pressure during spinal anesthesia
should be kept within 30% of the baseline value to prevent ischemia which may
prevent an injury to the spinal cord from recovering. It was also seen with spinal
microcatheters which lead to their discontinuation. It may also result from spinal
anesthesia in patients with preexisting spinal canal stenosis.40
Transient neurological syndrome (TNS) shows neurological symptoms which
are related to the area of spinal anesthesia. They are short lived and disappear
within 5 days. Usually there is intense burning pain followed by tingling and
paresthesias. TNS has been seen most commonly with lignocaine but has also
been seen with other local anesthetics. It is seen more commonly with higher
concentrations of local anesthetics which has lead to discontinuation of 5%
lignocaine solution for spinal anesthesia.41
Infections of the spinal cord such as meningitis occur due to exogenous or
endogenous source. It presents with fever, vomiting and signs of meningism.
Lumbar puncture reveals CSF which is turbid with raised leukocytes, proteins
and low glucose concentration. Treatment is with appropriate antibiotics.
Arachnoiditis is another complication which may be due to infection or
chemically induced by blood, local anesthetic or disinfectant solution. It may
present as TNS, cauda equine syndrome or conus medullaris syndrome.42
Apart from the complications of neuraxial blockade there are neurological
complications involving the cervical spine which have even more grave
consequences. These may be: quadriplegia or quadriparesis, Brown Sequard
syndrome, central cord syndrome and even death. The patients who have
maximum anesthetic risk are those with cervical spine fracture or instability
undergoing laryngoscopic intubation as it involves cervical spine motion
which results in critical cord compression. Concerns regarding cervical spine
injury during intubation have caused a significant shift in practice towards use
of video laryngoscopes, fiberoptic intubation and use of supraglottic devices.
Cervical cord injury may also result from cervical spine surgery due to direct
cord injury, hypotension or positioning of the neck. The sitting position has been
associated with a high incidence of cervical cord injury. Cervical spine instability,
stenosis and spondylosis may contribute to its occurrence. It is usually detected
immediately after the procedure and requires specialized management.43
CRANIAL NERVE INJURIES

Palsies of 6th and 7th cranial nerve may be seen following continuous CSF leak
after dural puncture presenting as diplopia and hearing loss.44 Cranial nerve
palsies are seen with blocks for ophthalmic surgery. Damage to optic nerve,
brainstem anesthesia with blockade of the eighth to twelfth cranial nerves is
seen. This may result in deafness, tinnitus, vertigo, dysarthria, dysphagia, and
aphasia. Mostly the patient recovers fully but the palsy may persist.45 Cranial
nerve palsies have been seen following surgeries in the area of the neck such as
carotid endarterectomy, neck dissection, thyroid surgery and mastoid surgery.46
Cranial nerve palsies (CNP) have been as a complication of airway intervention.

Supraglottic devices have been associated more commonly with cranial nerve
palsies but there are case reports of endotracheal intubation resulting in CNP.
The most commonly involved nerve is the lingual nerve followed by the recurrent
laryngeal nerve, hypoglossal nerve, glossopharyngeal nerve, inferior alveolar
nerve and infraorbital nerve. Palsy usually results from pressure neuropraxia.
Factors leading to it are: inappropriate size or misplacement of the supraglottic
device, patient position, overinflation of the cuff resulting in high pressure and
poor insertion technique. These injuries are usually mild and self-limiting. Injury
to the recurrent laryngeal nerve may persist resulting in serious consequences.47
PERIPHERAL NERVE INJURIES

Nerve injuries have been seen after all nerve blocks but they are extremely rare.
The type of nerve blockade influences the outcome of blockade with some nerve
injuries resulting in permanent sequelae. Early manifestations are transient
postoperative neurologic symptoms which are common in the first few days
to about a month after the nerve block. The factors associated with peripheral
nerve injuries (PNI) due to neural blockade are: eliciting of paresthesias,
peripheral nerve stimulation, high concentration of local anesthetic and
increased intrafascicular speed of injection. The Second ASRA Practice Advisory
on Neurologic Complications in Regional Anesthesia and Pain Medicine has
recommended the use of ultrasound as part of vigilant care for locating nerves
during PNI. The incidence of PNI has decreased considerably with the use of
ultrasound guided techniques and measurement of pressure during injection of
drug. They need to be differentiated from nerve injuries due to the surgery as
they share the same anatomical nerve distribution. These are commonly seen
after orthopedic surgeries of the hip, shoulder, knee and elbow. Perioperative
nerve injury has been associated with preexisting diseases such as hypertension,
peripheral vascular disease, vasculitis and smoking. The presence of neurological
disease places the patient at a higher risk of PNI.48
There are many PNI associated with general anesthesia also. These injuries
are associated with poor positioning of limbs with inadequate padding, resulting
in stretching and compression of the nerves. The commonly affected nerves are:
radial, ulnar, axillary and median nerves and the brachial plexus in the upper
limbs and the sciatic, femoral and superficial nerves in the lower limbs. Spine
surgery is associated with a high incidence of PNI as it is done in the prone
position and requires very careful positioning. Surgical retraction can also result
in PNI by the same mechanism. Tourniquet neuropathy is another cause of PNI.
It is associated with prolonged inflation of tourniquet and increased tourniquet
pressures.49
CONCLUSION
The neurological complications of anesthesia and surgery can occur in a range
of settings. Knowledge of these complications can help the anesthesiologist to
prevent them from occurring and in diagnosing the conditions when they occur
inspite of best practice and help in treating them.
KEY POINTS
• B oth surgery and anesthesia are associated with neurological complications.
• Complications such as delirium and postoperative cognitive dysfunction can be very
distressing for the relatives and prolong the hospital stay of the patient.
• Postoperative visual loss and stroke can be debilitating and life changing for the patient.
• Neuraxial injuries can result in distressing complications such as cauda equine
syndrome and paraplegia.
• Peripheral nerve injuries are seen after poor positioning under general anesthesia,
use of tourniquet, direct injuries to the nerves due to surgery as well as nerve blocks
administered by anesthesiologists.
• Use of modalities such as use of ultrasound can prevent nerve injuries resulting in
sensory and motor deficits which may take a long time to recover.
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Anesthesiol. 2014;26:273-85.
31. Perks A, Cheema S, Mohanraj R. Anaesthesia and epilepsy. Br J Anaesth. 2012;108:
562-71.
32. Gueli SL, Lerman J. Controversies in pediatric anesthesia: sevoflurane and fluid
management. Curr Opin Anesthiol. 2013;26(3):310-7.
33. Zuleta-Alarcon A, Castellon-Larios K, Moran KR, Soghomonyan S, Kurnutala LN,
Berghese SD, Anesthesia related perioperative siezures: pathophysiology, predisposing
factors and practical recommendations. Austin J Anesthesia and Analgesia. 2014;
2(4):1-9.
34. Prakash S, Mehra V, Gogia AR. Fentanyl induced rigidity in an infant. J Anesthesiol Clin
Pharmacol. 2010;26:567.
35. Neal, Joseph M, Bernards, Christopher M, Butterworth, John F IV, et al. ASRA practice
advisory on local anesthetic systemic toxicity. Reg Anesth Pain Med. 2010; 35(2):152-61.
36. Volk T, Wolf A, Van Aken H, Bürkle H, Wiebalck A, Steinfeldt T. Incidence of spinal
haematoma after epidural puncture: analysis from the German network for safety in
regional anaesthesia. Eur J Anaesthesiol. 2012;29(4):170-6.
37. Sánchez Gutiérrez C, Alemán Martín A, Coronado Hijón V, et al. Spontaneous
resolution of a paraparesis due to a dorsolumbar epidural haematoma associated with
subarachnoid anaesthesia and postoperative analgesia using an epidural catheter. Rev
Esp Anestesiol Reanim. 2012;59(9):503-6.
38. Tumber SS, Liu H. Epidural abscess after multiple lumbar punctures for labour
epidural catheter placement. J Biomed Res. 2010;24(4):332-5.
39. Jain M, Srivastava U, Saxena S, et al. Cauda equina syndrome following an uneventful
spinal anesthesia. Indian J Anesth. 2010;54:69-9.
40. Goyal LD, Kaur H, Singh A. Cauda equina syndrome after repeated spinal attempts:
A case report and review of the literature. Saudi J Anaesth. 2015;9:214-6.
41. Zaric D, Pace NL. Transient neurologic symptoms (TNS) following spinal anaesthesia
with lidocaine versus other local anaesthetics. Cochrane Database Syst Rev.
2009;(2):CD003006.
42. Agarwal A, Kishore K. Complications and controversies of regional anaesthesia:
A review. Indian J Anaesth. 2009;53:543-53.
43. Hindman BJ, Palecek JP, Posner KL, Traynelis VC, Lee LA, Sawin PD, Tredway TL, Todd
MM, Domino KB. Cervical spinal cord, root, and bony spine injuries: A closed claims
analysis. Anesthesiology. 2011;114(4):782-95.
44. Nishio I, Williams BA, Williams JP. Diplopia: A complication of dural puncture.
45. Jaichandran V. Ophthalmic regional anaesthesia: A review and update. Ind J Anaesth.
2013;57(1):7-13.
46. Chee VK. Facial palsy after carotid endarterectomy and difficult intubation during
subsequent CABG surgery: An impact of the cranial nerve injury on airway
management. IJAR. ISSN 2332-780.
47. Thiruvenkatarajan V, Van Wijk RM, Rajbhoj A. Cranial nerve injuries with supraglottic
airway devices: a systematic review of published case reports and series. Anaesthesia.
2015;70:344-59.
48. Neal JM, Barrington MJ, Brull R, Hadzic A, Hebl JR, Horlocker TT, Huntoon MA, Kopp
SL, Rathmell JP, et al. The second ASRA practice advisory on neurologic complications
associated with regional anesthesia and pain medicine: Executive summary 2015.
Regional Anesthesia and Pain Medicine. 2015;40(5):401-30.
49. Lalkhen AG, Bhatia K. Perioperative peripheral nerve injuries. Contin Educ Anaesth
Crit Care Pain. 2012;12:38-42.
CHAPTER 22
Perioperative Beta Blockers:
To Use or Not to Use
Yatin Mehta, Ajay Kumar
INTRODUCTION
Perioperative major adverse cardiac events (MACEs), i.e. cardiac death, nonfatal
cardiac arrest, acute myocardial infarction (MI), congestive heart failure, and
angina have been an Achilles heel for both cardiac and noncardiac surgery.
Surgery for acquired cardiac disease has a mortality rate of 3%, perioperative
myocardial infarction of 6% and all cause complication rates of 15% to 24%.1
On the other hand, myocardial injury after noncardiac surgery (NCS), although
very high is still under appreciated by clinicians.2 According to an estimate there
are over 200 million annual surgeries done worldwide and approximately half
involve patients over 45 years and at significant risk (8%) of myocardial injury.3
Thirty-day mortality is 11.6% among patients with perioperative myocardial
infarction, resulting in more than 8,00,000 deaths.4 Amongst the multiple
strategies employed to improve the perioperative outcomes in both groups, none
is so simple and yet associated with more controversies than the use of beta
blockers. Beta blockers are one of the common drugs prescribed for patients at
risk of cardiovascular events from the active treatment of coronary artery disease
and congestive heart failure to control of sympathetic response in noncardiac
surgeries. Yet, in the perioperative arena, their use is mired by a few studies and
multiple recent changes in the guidelines.
BENEFICIAL EFFECTS OF BETA BLOCKERS

Perioperative cardiovascular death has been attributable to stress of surgery,
which is due to increased sympathetic response and imbalance in oxygen
supply and demand. Other different causes are plaque rupture, thrombosis
and occlusion.5 Use of beta blockers has multiple favorable effects, thereby
improving the outcome (Table 22.1). Anti-ischemic effect can be explained by
the negative effect on inotropic and chronotropic actions that decrease oxygen
requirement, as a result of which it can withstand decreased blood supply without
experiencing ischemia.6 They stabilize plaques and prevent asymptomatic
plaques from rupturing They also carry anti-arrhythmic and anti-renin effect.7
It inhibits recruitment of myocytes and release of cytokines, thereby modulating
inflammatory response,8 which have been attributed for recent finding of
association of long-term beta blocker therapy and decreased mortality in septic
patients.9 It improves cell survival by decrease in rate of apoptosis.10
Perioperative Beta Blockers: To Use or Not to Use 255
Table 22.1 Potential cardioprotective effects of beta blockers

1. Decreased oxygen demand
2. Increased diastolic perfusion time6
3. Suppresses arrhythmia5
4. Stabilizes plaque7
5. Anti-inflammatory responses8
6. Inhibits apoptosis10
McSPI and DECREASE I: The Edifice

Evidence in favor of the use of beta blockers started appearing in mid-90s.
Multicenter Study of Perioperative Ischemia (McSPI)11 and Dutch
Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography
(DECREASE) I were amongst the pioneer studies to demonstrate importance of
beta blocker in reducing major adverse cardiac events (MACE) in perioperative
period. Mangano et al. randomized 200 patients with coronary artery disease
undergoing noncardiac surgery to receive intravenous atenolol or a placebo
just prior to induction and continued into the postoperative period.11 They
observed a significant decrease in all-cause mortality at 2 years by risk ratio
of 14 and reduction in nonfatal cardiac complications. The DECREASE I12
study demonstrated a mortality benefit from cardiac causes and nonfatal
myocardial infarction (MI) within 30 days. Both the studies were criticized for
small size, with minimum power of highly screened population. When large
and adequately powered studies metoprolol after vascular surgery (MaVS)13,
diabetic postoperative mortality and morbidity (DIPOM)14 and perioperative
beta blockade (POBBLE)15 were done, they did not show any association of either
improved outcomes with respect to MACE or a mortality benefit.
Perioperative Ischemic Evaluation (POISE) Trial: The Pause Effect

To ward off skepticism and growing conflicting evidence, a very large study
was commissioned involving >8000 patients spread over 23 countries with
atherosclerotic diseases undergoing NCS simultaneously over a period of
time to assess 25% relative risk reduction in MACE.16 Over a 30-day period,
there were lower MACE in metoprolol (5.8% vs 6.9%, HR 0.84, CI 0.70–0.99;
p=0.0399), Myocardial infarction (4.2% vs 5.7%, HR 0.73, CI 0.60–0.89;
p=0.0017), Interestingly, there were more deaths (3.1% vs 2.3% HR 1.33, 1.03–
1.74; p=0.0317) and stroke (1.0% vs 0.5% HR 2.17, 1.26–3.74; p=0.0053) in the
metoprolol group. Metoprolol group had significant hypotension, bradycardia
intraoperative and immediate postoperative period and stroke which was
attributed to mortality. Stroke has been attributed to poor control of central
aortic pressure. 17 Increased incidence of sepsis was attributed to hypotension
resulting in increased risk of infection. The study was criticized for aggressive
dosing (200 mg per day), expeditious use of beta blocker in perioperative
period, inadequate dose titration, poor drug selection and inclusion of urgent
and emergent cases.
POST POISE: The Course Correction

In 2014, American Heart Association (AHA) updated its guideline18 in view of
POISE trial and controversy arising out of authenticity of DECREASE studies. It
downgraded the recommendation of beta blocker from “reasonable” to “may be
considered” in view of weakened evidence without Polderman data in high and
intermediate risk patients. But, its still recommended “may be considered” in
view of nonrandomized studies.
BETA BLOCKERS AND NONCARDIAC SURGERY

The advantage of using beta blocker medications during the perioperative
period is directed at decreasing stress-induced myocardial ischemia in patients
undergoing major operations, such as vascular surgery, who are at increased risk
for adverse cardiac events. American Heart Association had also recommended
class IIa indication for that in 2009. There is no doubt about continuing beta
blocker therapy in patients who are already on it for longitudinal indications
myocardial infarction. Discontinuation of it may lead to sudden upregulation of
beta receptors leading to spurt in blood pressure, risk of plaque dislodgement
and MACE. There is definite protective effect of beta blockers against acute MI
and myocardial ischemia.19 Ischemic episodes can trigger ventricular rhythm
disturbance, and a reduction in ischemia could account for the reduced rate
of ventricular arrhythmias seen in patients taking beta blockers.19 Even when
primary outcomes from the POISE trial were stratified by procedure type, patients
undergoing vascular surgery were found to receive a far greater benefit from
other procedures.16 Vascular surgeries expose perioperative risk more overtly
than any other noncardiac surgery. In view of questions raised about increased
risk of other events, i.e. stroke and mortality, myocardial protective action has
taken a backseat.
Debate lies, however, in whether these agents affect the risk of death after
surgery. The results of more contemporary studies suggest that patients may
actually have a higher risk of all-cause mortality while taking these agents
(Table 22.2). It may result from the increased risk of adverse perioperative events
Table 22.2 Important studies and key findings on beta blocker therapy in noncardiac surgery
Study Year Outcome Beta- Placebo % Stroke
blocker (%)
Beta Placebo
blocker
Mangano11 1996 MI/Death at 2 yrs 10 21 4 1
Polderman12 1999 MI/Death at 28 days 3.4 34
POISE16 2008 MI 3.6 5.1 1.0 0.5
Death 3.1 2.3
London5 2013 MI 1.3 2.3 0.4 0.3
Death 0.8 2.1
Bouri 2013 MI 0.60 0.39
Death 3.5 4.7
such as hypotension, bradycardia, and stroke associated with beta blocker over
treatment. Mortality benefits shown in earlier studies were mainly from reduced
cardiac events postoperatively and reduced 30-day mortality.11,12 London MJ
in his study noted that beta blocker was associated with lower rates of 30-day
mortality (relative risk [RR] 0.73, 95% confidence interval [CI] 0.65–0.83, P < .001)
as well as a lower rate of cardiac morbidity in patients with 2 or more revised
cardiac risk index (RCRI). The findings support the cumulative numbers of
predictors in decision making regarding initiation and continuation of beta
blocker. All-cause mortality and morbidity caused by stroke were not analyzed.
A study has emphasized the nonmodifiable factors which predispose them to
more risk of stroke, have to be considered while prescribing beta blockers, i.e.
age, cardiac history, female sex, history of cerebrovascular accident and acute
renal failure or dysrhythmia.20 Recent studies by Friedell21 and colleagues
endorsed other findings that beta blockade was beneficial perioperatively in
patients of high cardiac risk (>3 risk factors). It had no effect on patients having
1–2 risk factors. In contrast, beta blockers in patients with no cardiac risk factors
undergoing noncardiac surgery increased risk of death perioperatively.
In a study on the impact of perioperative bleeding on the protective effects
of beta blockers during infrarenal aortic reconstruction, Le Manach22 et al.
observed reduction in cardiac events in vast majority of patients. But patients
who had severe blood loss had higher mortality and multiorgan dysfunction
syndrome. Among the patients who expired, 28% had MI, whereas 69% of the
MI had excessive bleeding. This emphasizes that patients on beta blocker having
higher bleeding risk have high risk of mortality and multiorgan dysfunction. Beta
blockers cannot be implemented off hand in each and every patient. So, clinician
role comes into play whether to go for beta blocker in patients having high risk of
bleeding and revising the threshold level of hemoglobin at which transfusion is to
be initiated.
BETA BLOCKERS AND CARDIAC SURGERY

Current evidence supports the use of beta blocker therapy to improve maladaptive
left ventricular (LV) remodeling in medical management of early stage of heart
failure (stage B) and low LVEF (stage c) to improve morbidity and mortality.23 Beta
blockers reduce the risk of death and combined risk of death or hospitalization in
patients of low LVEF with or without coronary artery disease.24
Such a definitive relationship of better outcome of therapy in medical
management of heart failure led us to speculate it to be beneficial in patients
undergoing CABG. Efficacy of beta blockers in cardiac surgery is difficult to
observe because the trauma of coronary artery bypass operation itself may
constitute a major determinant in developing AMI in these patients rather than
the sympathetic response on increased oxygen demands.19 Observational studies
conducted by Ferguson25 et al. the patients undergoing CABG, who received
beta blockers had lower 30-day mortality, 2.8% vs 3.4%, than who did not. The
aforementioned study identified predictors of use of beta blockers that included
recent myocardial infarction, hypertension, angina, younger age, left ventricular
systolic function >30%, absence of congestive heart failure, chronic lung disease,
and diabetes. This study lead to rapid adoption of beta blocker in CABG patients.
Beta blockers use is prevalent in 92% of patients undergoing CABG.26 Beta blocker
therapy has been considered as a quality metric in hospitals providing CABG.27

Banglore S observed that primary outcome in terms of nonfatal MI, stroke, or
cardiovascular mortality was lower by 31% at 28 months of follow-up driven
mainly by lower risk of recurrent MI with no difference in all-cause mortality
in group with prior MI but no heart failure. In the two other groups with known
atherothrombotic disease and the risk factors alone cohorts, it was not associated
with lower ischemic outcomes.28 Overall mortality benefit is observed in limited
set of population, i.e. patients with prior MI and not all CAD patients or low risk
patients as projected earlier.
Their efficiency in preventing and treating perioperative MI is supported by
the results of observational studies and small randomized trials29,30 although a
meta-analysis31 and a recent observational study by Society of Thoracic Surgeons
(STS)26 did not show any improvement in perioperative outcome with beta
blockers.
Postoperative atrial fibrillation (AF) occurs in 25% to 50% of patients after
open heart surgery.32 Postoperative AF is associated with stroke, increased cost
and mortality. According to Crystal et al. beta blockers reduced the odds of
developing postoperative atrial fibrillation by 61% (OR 0.39, 95% CI 0.28 to 0.52).32
Citing this STS has recommended class Ib recommendation for beta blockers in
CABG for prevention and treatment of AF.33 An observational study conducted on
patients who were not having MI in 21 days before surgery found that AF was more
common in patients who were taking beta blockers and there was no effect on
mortality and morbidity.25 This study has been questioned about non-inclusion
of recent MI in beta blocked, and inclusion of patients taking amiodarone in
non beta blocked group, which has proven effect on AF.34 There is protective
effect of beta blocker on occurrence of ventricular tachycardia and ventricular
fibrillation.35 Data suggest that beta-blockers effectively prevented deterioration
in ventricular tachycardias and fibrillation, as ventricular extra beats are known
to spark off these tachyarrhythmias. Bradycardia is not commonly seen in
patients of cardiac surgery due to beta blocker therapy. Slowing down heart rate
is an intrinsic effect of indexed drug, patients undergoing cardiac surgery are
under tight hemodynamic control, and doctors probably are more determined
to keep these hemodynamic variables stable within a small range. Control of
heart rate and blood pressure is much tighter in beta blocker therapy, finding of
hypotension as a result of it has not been done on large sample size and effects of
confounders are high.
Increased risk of cerebrovascular events was reported in a study conducted
in cardiac surgical patients with metoprolol in perioperative period (RR2.33
CI 0.66 to 8.97).36 However, the technique of surgery has its own impact.
Macroembolization, microembolization, use of extracorporeal cardiopulmonary
bypass during surgery and manipulation of the aorta during surgery are the major
reasons of cerebrovascular events after heart surgery.33
Intermediate and long-term efficacy of beta blocker after hospital discharge is
uncertain. Two randomized trials and an observational study have shown that it
does not exert any benefit over two years.37,38 Whereas studies have reported it to
be effective in perioperative MI or elderly with heart failure.39 In a study by Zhang
et al. patients with or without previous MI undergoing CABG, beta blocker was
associated with a lower risk of long-term mortality and adverse cardiovascular
events in patients taking it consistently.40 Another study has reported reduced

mortality in patients taking beta blocker over 75 months follow up.41 It is common
consensus to continue beta blocker postoperatively at the time of discharge in the
patients not having any contraindication to it.33
In a double blind trial, beta blockers have not been seen to improve exercise
capacity and increase maximal oxygen consumption despite reduction in heart
rate by 20% and increase in diastolic filling period by 40%.42 There was hardly
any change in stroke volume index. Despite decrease in transvalvular gradient,
there was hardly any benefit in exercise performance. However, American Heart
Association43 has recommended beta blockers in class IIb in selected patients
with decreased exercise capacity with a target of control in heart rate and
decreased transvalvular gradient.
In congenital heart disease,44,45 i.e coarctation of aorta, beta blockers have
been recommended for control of hypertension. In tetrology of Fallot, it relaxes
the contracted infundibulum and to allow more time for right ventricular filling,
improving pulmonary blood flow. Preoperative use of propranolol leads to
decrease in junctional rhythm in patients of tetralogy.
BETA BLOCKERS FORMULATION AND TITRATION

Beta blocker formulations have three major concerns—choice of drug, its dose
and time of initiation. Beta blockers, effective in reducing the risk of death in
patients with chronic heart failure include sustained release metoprolol which
selectively blocks beta-1 receptors. Carvedilol, which blocks alpha-1, beta-1, and
beta-2 receptors is effective as dilator also reducing systemic vascular resistance
and helps unloading the left ventricle. Studies evaluating specific beta blocker,
cardioselective agent bisoprolol and atenolol were associated with better
outcomes than metoprolol.46 Nebivolol demonstrated a reduction in the all-cause
mortality or cardiovascular hospitalization but did not affect mortality alone in
patients of heart failure.47 It has been found to have same reduction in brachial
blood pressure. But decreases in aortic pulse pressure more than atenolol has
been found to be associated with higher rates of strokes and mortality in recent
trials.48 Nebivolol and bisoprolol have shown promising results but more RCC
studies are required.
Studies have shown that beta blockers started a week before surgery and
titrated to response have better outcome.12 But more studies are required
to conclusively say that prior dosing more than 24 hours before surgery has
beneficial association or no effect.
High doses have been implicated for more number of adverse events seen.16
However, lower starting dose in three studies saw neither harm nor any benefit.
In clinical practice beta blocker dose achieved is usually 50% of the desired target
dose. Once a beta blocker is initiated, its dose remains the same as initiating dose.
In a day-to-day clinical practice, dose of metoprolol succinate hardly exceeds
100 mg, which was far less than 200–400 mg administered in POISE trial.
CONCLUSION
Despite sceptics questioning the benefits of perioperative beta blockers, even
associating it as a cause of increased incidence of stroke and mortality, beta
blockers in perioperative care have withstood till date. Adverse cardiac events
in noncardiac surgery, including cardiac cause of mortality in perioperative and
early convalescence period, have decreased, though the drug has been restricted
to patients having higher revised cardiac risk indices. It has been valuable in
prevention and treatment of perioperative arrhythmia and ischemia. Factors
predisposing patients to enhanced risk of stroke have to be considered before
commencing beta blockers. There is mortality benefit in patients having three or
more risk factors predisposing to adverse cardiac events.
In cardiac surgeries, beta blockers have been found to be efficacious in
prevention of early hospital, intermediate and long-term mortality. It is gainful
in patients of coronary, valvular and congenital heart disease with less adverse
events. It is helpful in prevention and treatment of arrhythmia in perioperative
period in coronary artery disease and valvular heart disease. New agents, i.e.
nebivolol and bisoprolol have been more accepted with less adverse events.
Increased incidence of stroke has been attributed to other causes, which are
more rational. Overall, beta blocker has been found to be beneficial in cardiac
and noncardiac surgery.
KEY POINTS
In Noncardiac Surgery
• Beta blockers should be titrated against hemodynamics over a period of days before
surgery.
• They are protective against myocardial ischemia and have preventive and therapeutic
benefits in arrhythmia.
• They decrease incidence of mortality due to cardiac cause, however, factors predisposing
to higher risk of stroke have to be considered.
In Cardiac Surgery
• They are used to prevent and treat perioperative arrhythmia in CABG and valvular heart
disease.
• They are beneficial in recent myocardial infarction, age <75 years, ejection fraction
≥ 30%.
• New agents nebivolol and bisoprolol are more effective.
• Mortality benefit of beta blockers has been conclusively proven in large studies.
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33. Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG, Cigarroa JE, Disesa
VJ, Hiratzka LF, Hutter AM Jr, 2011 ACCF/AHA Guideline for Coronary Artery Bypass
Graft Surgery: executive summary: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice Guidelines.
Circulation. 2011;124(23):2610-42.
34. Shahian DM. Preoperative β-blockade in coronary artery bypass grafting surgery.
JAMA Intern Med. 2014;174(8):1328-9.
35. Auer J, Weber T, Berent R, Puschmann R, Hartl P, Ng C, et al. A comparison between
oral antiarrhythmic drugs in the prevention of atrial fibrillation after cardiac surgery:
the pilot study of prevention of postoperative atrial fibrillation (SSPAF), a randomized,
placebo-controlled trial. American Heart Journal. 2004;147(4):636-43.
36. Connolly SJ, Cybulsky I, Lamy A, Roberts RS, O’brien B, Carroll S, Crystal E, Thorpe
KE. Double-blind, placebo-controlled, randomized trial of prophylactic metoprolol for
reduction of hospital length of stay after heart surgery: the beta-blocker length of stay
(BLOS) study. Am Heart J. 2003;145(2):226-32.
37. The MACB Study Group. Effect of metoprolol on death and cardiac events during a 2–
year period after coronary artery bypass grafting. Eur Heart J. 1995;16:1825-32.
38. Goyal A, Alexander JH, Hafley GE, et al. Outcomes associated with the use of secondary
prevention medications after coronary artery bypass graft surgery. Ann Thorac Surg.
2007;83:993-1001.
39. Chen J, Radford MJ, Wang Y, et al. Are beta-blockers effective in elderly patients who
undergo coronary revascularization after acute myocardial infarction? Arch Intern
Med. 2000;160:947-52.
40. Zhang H, Yuan X, Zhang H, Chen S, Zhao Y, Hua K, Rao C, Wang W, Sun H, Hu S,
Zheng Z Circulation. Efficacy of Long-Term β-Blocker Therapy for Secondary
Prevention of Long-Term Outcomes After Coronary Artery Bypass Grafting Surgery.
2015;131(25):2194-201.
41. Chan AY, McAlister FA, Norris CM, et al. Effect of beta-blocker use on outcomes after
discharge in patients who underwent cardiac surgery. J Thorac Cardiovasc Surg.
2010;140:182-7.
42. Stoll BC, Aschcon TL, Johns JP. Effects of atenolol on rest and exercise hemodynamics
in patients with mitral stenosis. Am J Cardiol. 1995;75(7):482-4.
43. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, O’Gara
PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt TM 3rd, Thomas JD;ACC/AHA Task Force
Members. 2014 AHA/ACC guideline for the management of patients with valvular heart
disease: a report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines. Circulation. 2014;129(23):2440-92
44. Nishimura RA, Otto CM, Bonow RO, Carabello BA, et al. American College of Cardiology/
American Heart Association. J Thorac Cardiovasc Surg. 2014;148(1):e1-e132.
45. Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA, del
Nido P, American College of Cardiology; American Heart Association Task Force
on Practice Guidelines. ACC/AHA 2008 guidelines for the management of adults
with congenital heart disease: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines. Developed in
Collaboration With the American Society of Echocardiography, Heart Rhythm Society,
International Society for Adult Congenital Heart Disease, Society for Cardiovascular
Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol.
2008;52(23):e143-263.
46. Ashes C, Judelman S, Wijeysundera DN, et al. Selective beta-1-antagonism with
bisoprolol is associated with fewer postoperative strokes than atenolol or metoprolol:
a single-center cohort study of 44,092 consecutive patients. Anesthesiology. 2013;
119:777-87.
47. Van Veldhuisen DJ, Cohen-Solal A, Bohm M, et al. Beta-blockade with nebivolol in
elderly heart failure patients with impaired and preserved left ventricular ejection
fraction: data from SENIORS (Study of Effects of Nebivolol Intervention on Outcomes
and Rehospitalization in Seniors with Heart Failure). J Am Coll Cardiol. 2009;53:2150-8.
48. Dhakam Z, Yasmin, McEniery CM, Burton T, Brown MJ, Wilkinson IB. A comparison of
atenolol and nebivolol in isolated systolic hypertension. J Hypertens. 2008; 26(2):351-6.
CHAPTER 23
Biomarkers in Anesthesiology
Kamal Fotedar
INTRODUCTION
Biomarkers are a measure of biological state. It has been defined as “cellular
biochemical or molecular alteration that are measureable in biological media
such as human tissue, cells or fluid.1 In 1998, the National Institute of Health
biomarkers Definition Working Group defined Biomarker as “ A characteristic that
is objectively measured, evaluated as an indicator of normal biological process,
pathogenic process, or pharmacological response to a therapeutic intervention.”2
Biomarkers help not only in disease diagnosis, but also help to chart progress
during the course of the disease, prognostication and outcome after intervention.
Biomarkers can be a molecule of protein, lipid, gene, enzyme or hormone.
It may even be a metabolite or alteration of biological structure or its feature.3
Biomarkers can be classified as marker of exposure where they are related to risk
prediction or as marker of disease, where they are used for screening, diagnosis or
monitoring of its progression.4
Biomarkers have been undergoing investigations by epidemiologists and
physicians to study history, diagnosis and prognosis of disease. Most importantly
it helps physicians to delineate the events between exposure and disease thereby
lending the potential to identify earliest events.
Characteristics of an ideal biomarker are:5
• It should have high sensitivity with organ specificity.
• It should be immediately released with tissue injury.
• Release should be proportional to insult.
• For it to be predictive, it should have long half-life.
• For it to qualify as a monitoring tool, its concentration should decrease quickly.
• Its measurement should be rapid, simple, accurate and inexpensive.
• It should be noninvasive and accessible.
Acute care physicians in setting of critical care and operation theater are
concerned about optimum functioning of organs, which are prone to injury
insult subsequent to adverse event. Early detection of latent injury can prevent
irreversible damage and, therefore, biomarkers of heart, kidney, gut, brain sepsis
assume importance in clinical practice.
Biomarkers in Anesthesiology 265
BIOMARKERS OF CARDIOVASCULAR SYSTEM

C-reactive Protein
Few biomarkers of disease have generated as much interest as C-reactive protein
(CRP). A hepatically derived pentraxin, it was discovered in 1930 by William
Tillet Thomas Francis of Rockefeller University in patient having pneumococcal
infection. CRP levels increase whenever there is inflammation in the body. High
sensitive C-reactive protein (hs-CRP) is used to evaluate risk of developing
coronary artery disease (CAD). Gunner Lofstrom in 1943 demonstrated hs-CRP’s
relationship with acute myocardial infarction. The American Heart Association
(AHA) does not recommend this test for general screening of people who are not
at high risk for heart disease, but hs-CRP should be considered for people who
have intermediate risk for having a heart attack in next 10 years. Those who are
at high risk for heart disease should be treated aggressively irrespective of their
hs-CRP levels. The other condition for which CRP is useful is rheumatoid arthritis
and lupus disease. It was described as acute phase reactant in inflammatory
diseases.6-8
Can hs-CRP be added to traditional cardiovascular risk factors? Ridker et
al. have recommended hs-CRP to be added as a clinical criteria for metabolic
syndrome in creation of a hs-CRP modified coronary risk score. Four studies
from the United States: the physician Health Study (PHS), women’s health
Study (WHS), Atherosclerosis Risk in Communities Study (ARIC) and Airforce/
Texas Atherosclerosis Prevention Study as well as 2 studies from Europe: the
Monitoring of trends Determinants of Cardiovascular Disease Study (MONICA),
and Reykjevik study suggests that hs-CRP gives better prognostication than other
markers. Farmingham Heart Study itself states that hs-CRP predicts thrombotic
events in cerebral circulation. Given the dependability and reliability of results,
creation of hs-CRP –modified cardiovascular heart disease (CHD) risk score is
useful for global risk prediction.9
Jones DML et al. in their correspondence criticized the results by Ridker et al.
arguing that the positive association between hs-CRP and cardiovascular events
showed a very small increment of at most 1–2% in area under curve (AUC). As
many other factors, e.g. renal failure causes elevation of CRP, it cannot be specific
prognosticating indicator.10 The Rotterdam study have presented data indicating
little increment value for CRP over and above the traditional risk factors. CRP
does not predict cardiovascular risk independent of other risk factors. According
to the Center for Disease Control (CDC) and the American Heart Association
Task Force, at best CRP may be used as a test for treatment decisions for patients
predicted to be at intermediate risk of developing cardiovascular disease.11
Cardiac Troponins
Troponin is a complex of three regulatory proteins integral to muscle contraction
in skeletal cardiac muscle, but not smooth muscle. Three types of cardiac
troponins are Troponin I (TnI), Troponin T (TnT) and Troponin C (TnC). Skeletal
TnI and TnT are structurally different from cardiac TnI and TnT, therefore,
immunoassays have been developed to differentiate them.
It is important to realize that troponins are not early biomarkers of myocardial

necrosis. For troponins to rise after myocardial infarction, it takes 8–12 hours. The
elevated levels remain for 7–10 days post-acute coronary event. Normal value
of Trop-I is <0.04 µg/L. Some cardiac etiologies for elevated Trop I are STEMI
and non-stemi, pulmonary embolism, myocardial contusion, myocarditis, heart
failure, tachyarrhythmias, implanted cardiac devices and electrocution. Non-
cardiac causes are shock, subarachnoid hemorrhage (SAH) and renal failure.
Elevated Trop-I identify patients at risk of adverse cardiac events, even in patients
with end stage renal disease (ESRD) without STEMI. With advent of high sensitivity
cardiac Troponin (hs-cTn), it is not recommended to wait for 6 hours but instead
it is safe to interpret results within 2 hours of coronary event. One should not
wait for Trop-I results in patients who present to emergency department for chest
pain and ST-segment elevated myocardial infarction (STEMI).12,13 They should
be referred immediately for thrombolysis and revascularization therapy without
delay.14
B-type Natriuretic Peptide

B-type natriuretic peptide (BNP) appears to be new revolutionary investigation
in congestive cardiac failure. It promises to differentiate between dyspnea of
cardiac origin from that of pulmonary origin. Normal value of BNP can rule out
congestive heart failure (CHF) as contributing factor for patient’s dyspnea.
BNP is one of three naturally occurring peptides; A-type (ANP) and C-type
(CNP), being the other two. BNP is released from left ventricular myocytes in
response to volume pressure loading. Dao et al. using point of care assay of BNP
(n=250) were able to differentiate the cutoff value of BNP as 80 picogram/L as
very specific and sensitive measure between CHF patients (n=97) with BNP
value 1078±138 picogram/mL vs non-CHF patients (n=139) with BNP value 38 ±
pictogram/mL.15 Biccard et al. tried to analyze whether BNP levels were superior
to other risk predictors, e.g. CRP, troponins or myocardial ischemia monitoring, in
a subset of cardiac patients for elective vascular surgery, and concluded that the
preoperative BNP levels were useful predictors of postoperative complications.16
BNP has been shown to be a strong prognostication and risk stratification
marker. Higher BNP values are associated with worse prognosis. It should not be
used as a stand-alone test. A relative risk at 6 months for CHF was 24 with BNP
values >230 picogram/mL.17
Nondiagnostic range of BNP levels 100–150 ngm/L should be seen in light of
clinical picture with other factors influencing BNP levels, e.g:
• Increasing age
• Higher with patients having atrial fibrillation
• Obesity
• Anemia
• Patients on nesiritide.
Soluble Urokinase Plasminogen Activation Receptor

About 15–20% patients do not have demonstrable conventional risk factors such
as hypertension, diabetes, age, etc. Biomarkers such as hs-CRP, BNP have been
around for sometime. Considering the role of inflammation in cardiovascular
disease, Soluble urokinase plasminogen activation receptor (suPAR), a

membrane-linked protein involved in regulation of atherogenesis is the new
marker on horizon for detecting subclinical levels of inflammation.18 High levels
of suPAR are associated with increased risk for cancer, cardiovascular disease
(CVD), diabetes mellitus (DM) and mortality.19 When suPAR and CRP was added
with adjustment of Farmingham risk score, it resulted in stronger risk prediction
for cardiovascular disease.20
Numerous studies have shown suPAR to be associated with cancer, infection,
inflammation, rhematoid arthritis, and hepatic fibrosis. suPAR has a role to play
in critical illness sepsis. Koch et al. found that suPAR levels were higher in patients
with sepsis than the control group. Area under receiver operative characteristic
curve (AuROC) for suPAR vs CRP vs procalcitonin was 0.62 vs 0.86 and 0.78
respectively. So the diagnostic ability of suPAR was doubtful.21
BIOMARKERS OF KIDNEY INJURY

Unlike cardiac biomarkers, the pace in development of kidney biomarkers has
been slown. Ischemia, contrast dyes, nephrotoxins and bacterial endotoxins are
triggers for acute kidney injury (AKI). The not-so-good outcome in AKI is because
of the fact that creatinine as a functional marker indicator does not change till
50% loss of kidney function. Early detection is impossible with serum creatinine
(SCr). Clinicians miss the opportunity to detect and treat AKI because of this time
differential.
Prior to 2004 multiple definitions of AKI made it difficult to compare and
compute results of research studies. This prompted Acute Dialysis Quality
Initiative (ADQI) in 2004–05 to develop RIFLE criteria. However, relationship
between SCr, urine output and pathophysiology of AKI is doubtful.22
Many genes are upregulated in injured kidney and appearance of protein
products in plasma urine can be used as marker of more timely diagnosis of AKI.
Biomarkers should lend us the ability to predict AKI. It is important to realize
the difference between “diagnosis of AKI vs early prediction of AKI” as it can
influence the outcome of AKI.23
Out of a number of biomarkers of kidney injury, e.g functional markers,
upregulated proteins, low molecular weight proteins and some enzymes, some of
the current ones are:
• Neutrophil gelatinase-associated lipocalin (NGAL)
• N-Acetyl-b-D-Glucosaminidase (NAG)
• Urinary cystatin C
• Plasma cystatin C
• Kidney injury molecule-1 (KIM-1)
• Interleukin 18 (IL-18)
Neutrophil Gelatinase-associated Lipocalin

Neutrophil gelatinase-associated lipocalin (NGAL) is a 25 kDa protein in
secondary granules of neutrophils. It is related to defense mechanism in human
tissue as it binds to siderophore (small iron binding molecule) needed by bacteria
for its growth, thereby preventing their growth. In kidney, it is expressed in distal
tubules and collecting ducts.
In children at risk of AKI, undergoing cardiopulmonary bypass, urinary NGAL

(u-NGAL) rose significantly within 2 hours post-bypass. These children
developed AKI within 24–48 hours, AuROC was near perfect at 0.998.24 While in
adult patients undergoing cardiac surgery, results were confounded by presence
of diabetes and renal dysfunction.25
Constantin et al. postulated that plasma NGAL (p-NGAL) rose 48 hours
before RIFLE criteria (n=88) in 1 month period. Using a cutoff of 155 nmol/L, the
sensitivity and specificity was 82% and 97% respectively. The AuROC was 0.92
(p=0.001).26 Urinary NGA (u-NGAL) or p-NGAL can be high in septic patient
irrespective of the presence of AKI. Both can be high due to severity of illness
and inflammation. In septic patients pre-existing AKI confuses the picture while
assessing role of NGAL in predicting AKI. NGAL concentration was raised more
than 80% in septic than nonseptic AKI patients. Between u-NGAL and p-NGAL,
the ability of former was more useful in predicting AKI, as its levels were not
elevated in septic patients without AKI.27-29
N-Acetyl-B-D-Glucosaminidase
This is a >130 kDa enzyme present in human tissues, kidney tubules being one
of them. Being a large molecule, it is difficult to get filtered from glomerulus. Its
origin in urine has been ascribed to tubular secretion.22 Out of 9 biomarkers which
were studied, NAG had an ability to identify established AKI with an AuROC of
0.83 thus predicting need for renal replacement therapy and mortality.30
Can a combination of biomarker improve prediction of AKI? Han et al.
postulated that a combination of kidney injury molecule (KIM-1) N-acetyl-B-D-
glucosaminidase (NAG) had no added value. When KIM-1, NAG and NGAL were
combined there was significant improvement in prediction.31 Similarly, liver-fatty
acid binding protein (L-FABP) NAG at 4 hours after surgery had a better AuROC
for prediction of AKI.32 In another study, Arthur et al. investigated 32 urinary
biomarkers (NAG being one of them) and found KIM-1 and Interleukin-18 (IL-18)
to be best predictor of death or AKI.33
Plasma and Urinary Cystatin-C (P-cystatin C and U-cystatin C)

At 13 kDa size, cystatin C is a proteinase inhibitor which enters proximal
tubule through glomerular filtrate. As cystatin is broken down in tubules and is
reabsorbed, very little is found in urine. In diseased state of kidney, the u-cystatin
C levels increase because of decreased reabsorption capacity of tubules.22
The results can be confusing in conditions where albuminuria accompanies
certain illnesses, because albumin competes with cystatin C thereby decreasing
absorption of latter. One such situation is sepsis where albuminuria and u-cystatin
levels are high. Such high levels can be confusing and, therefore, prediction of
AKI should be made with caution in some subgroup of critically ill patients.34
On the contrary p-cystatin C levels are better marker of glomerular filtration
rate (GFR) than SCr, as former is freely filtered, is less bound to protein and is
not absorbed after filtration. Since cystatin C molecule is larger than creatinine,
in situation of vasoconstriction in glomerular capilleries, creatinine molecule
being smaller, will be filtered more easily than cystatin C, whose levels will rise in
plasma. This makes a case for early rise of cystatin C in plasma than SCr.35
In a mixed ICU population, a > 50% increase in p-cystatin C values was shown
to predict AKI within 24 hrs (AUC 0.97).36 Harget-Rosenthal et al. tested diagnostic
accuracy of several enzymes including NAG, cystatin C, α1 and β2 micrglobulin,
LDH, etc. They found cystatin C and α1 microglobulin to be early predictors of
unfavorable outcome in ATN as reflected by requirement of RRT.37
In an observational study (n=200), it was seen that serum cystatin C, SCr,
serum urea nitrogen, or urine output performed similarly without any difference
in predicting dialysis requirement or death in AKI. The AuROC was 0.816,0.826,
0.837,0.836 respectively.38 However, Royakkers et al. in their study (n=151)
concluded that u-cystatin C and p-cystatin C levels on day 0 were poor predictors
for need of renal replacement therapy (RRT) in patients with AKI. (AUC < 0.66).
Even u-cystatin C had no diagnostic values 2 days prior to AKI development
(AUC < 0.50).39
BIOMARKERS OF GUT FAILURE

The quest to find biomarkers of gut barrier failure is as old as the concept that
barrier function loss in intestinal villi leads to translocation of bacteria leading
to development of multiorgan failure and its attendant morbidity and mortality.
Intestinal permeability is the capacity of some molecules like sugar and
electrolytes to move across mucosal layer of intestine. Intestinal barrier on the
other hand is what protects human being from bacterial attack. A single epithelial
cell called enterocyte forms the barrier with goblet cells secreting mucin and
paneth cell secretes α-defensin, and other antimicrobial peptides lysozymes and
phospholipases. Intestinal epithelium is renewed in approximately 5 days with
migration of enterocyte to top of intestinal villi from intestinal crypt through a
chain of proliferation, migration, maturation and finally apoptosis. The mature
enterocyte secretes citrulline.40
Translocation of bacteria from the gut lumen where they are in abundance,
stimulates macrophage leukocytes with subsequent release of cytokines like
interleukin, interferon and TNF-α leading to hypermetabolic state, a response
favoring systemic inflammatory response syndrome (SIRS) followed by multi-
organ failure (MOF). Deitch et al. in 1992 proposed “Two-hit phenomenon”. Initial
insult to body primes the body so that on a second insult the body response is
greatly exaggerated. In a clinical scenario, shock leading to ischemia of gut primes
the host for subsequent exaggeration to later insult such as translocated bacterial
endotoxins released into systemic circulation from intestinal lumen due to gut
barrier failure.41 In 2002, Deitch proposed “Three-hit model” theory whereby
first hit in form of visceral hypoperfusion causes release of pro-inflammatory
factors. With resuscitation the gut reperfusion leads to second hit. Once bacterial
endotoxin cross over from mucosa to portal circulation and thereafter systemic
circulation, there is enhancement of immune response with release of cytokines
and further injury leading to MOF or Third Hit.42
According to a new theory, the intestinal microflora has a role to play in critical
illness. This started with the discovery of membrane biosensor on pseudomonas
aeruginosa, which is activated by inflammatory modulators, leading to release of
Quorum Sensing Molecule (QS), once a critical density of bacteria is reached. A
system of virulent gene expression is activated, which stimulates Quorum sensing
circuitry. This circuitry in bacteria releases pro-inflammatory modulators leading
to increased permeability of intestinal epithelium, independent of translocation

of bacterial endotoxins.43,44
Citrulline Levels
The main source of citrulline is the intestinal enterocytes with glutamine as its
precursor. Citrulline reaches systemic circulation without metabolism in liver
with final destination being kidney for further metabolism. Here it undergoes
transformation into arginine, which is released into circulation. Normal values of
citrulline range from 20 µmol/L to 60 µmol/L. As biomarker of enterocyte mass,
citrulline levels below 20 µmol/L represent damage to enterocytes.45
Many investigators in their studies have shown that plasma citrulline
concentration decreases in critically ill patients who later have poor prognosis. It
is inversely related to CRP levels. Low levels of plasma citrulline and high levels
of Intestinal-Fatty acid binding protein (I-FABP) reflect intestinal epithelium
damage. Low levels also reflect bacterial translocation.46
Accuracy of citrulline levels are debatable because citrulline is dependent
on its precursor glutamine. As it gets metabolized to arginine in kidney, kidney
dysfunction can confound the results. Further, SIRS also has bearing on citrulline
levels. Since nitric oxide synthetase (NOS) transforms arginine to nitric oxide
(NO), citrulline. may be overmetabolized as a source of arginine, former’s
level may become low in SIRS. Citrulline levels may be high in acute renal
failure as citrulline is not being converted into arginine in these circumstances,
irrespective of enterocyte damage. Plasma citrulline concentration in critically
ill patients describe a U-shaped curve. Even if citrulline levels are low at the time
of admission, it is even lower 1–2 days later in ICU. It later increases in survivors.
So timing of sampling of citrulline should be taken into consideration while
interpreting results. When renal function is normal, decreased citrulline levels
reflect decreased synthesis. Values between 10 and 20 μmol /L is a grey zone for
interpretation, whereas < 10 μmol /L represents altered bowel function.47
Fatty Acid-binding Protein

Fatty acid-binding protein is a 14–15 kDa sized protein known since 1970.
Intestinal enterocytes hydrolyze dietary lipids and to achieve this capacity,
intestinal-fatty acid binding proteins (I-FABP) is crucial. Increased levels of
I-FABP are considered to be markers of bowel ischemia due to enterocyte
membrane rupture and release of I-FABP. Highly sensitive ELISA switch tests are
used to detect I-FABP. Mature enterocytes do not release I-FABP from cytoplasm.
Only when enterocytes are damaged, the plasma levels rise above 100 picogm/L.
It is seen that I-FABP is a dependable marker of acute mesenteric ischemia. It
is elevated early in ischemic injury to bowel even when histological damage is
mild.48
Relja et al. prospectively investigated 102 trauma patients and found I-FABP
levels to be higher in subjects with abdominal injury, as compared to those
without abdominal injury ( I-FABP levels 207pg/L) vs controls (I-FABP levels 108
pg/L). It could be used as a early biomarker for detecting significant abdominal
injury in multiple trauma.49
Procalcitonin
Procalcitonin (PCT) is a pro-hormone of calcitonin, but PCT and calcitonin are
two distinct proteins. PCT is a protein with 116 amino acids, a sequence similar
to that of prohormone calcitonin with 32 amino acids. Cacitonin is exclusively
produced by C-cells of thyroid gland in response to stimulation. PCT is produced
by several cell types and many organs in response to pro-inflammatory stimuli
produced by bacteria. Under normal conditions the levels of PCT are very low
in plasma (<0.05 ngm/mL). Significant concentration of PCT >1000 ngm/mL
can be seen in overwhelming bacterial infection. It increases within 6–12 hrs. of
stimulation.50
Procalcitonin helps to differentiate bacterial from viral infection. It helps to
assess the severity and prognosis of an infection. It supports early diagnosis of
sepsis. PCT has bactericidal properties with probable role in early defense against
infection during evolution of mammals. Now it has been replaced by more robust
defenses such as antibody system enhanced leukocyte defenses.51
Can PCT levels help clinicians to decide about diagnosis of infection and guide
in antibiotic decision making? Many observational studies found high diagnostic
performance of PCT. A cut-off of 0.1 µg/L had a high sensitivity to exclude
infection. Some studies postulated that PCT was able to differentiate between
blood stream infection and blood contamination. It had a better differentiation
compared to WBC and CRP.52,53
The PRORATA trial which published its results in Lancet demonstrated a
2.7 days reduction in antibiotic use with fewer subjects in PCT group received
antibiotic than control group (p<.0001). The group also suggested guidelines for
encouraging or discouraging antibiotics depending on level of PCT. With levels
<0.25 µg, between > 0.25 and <0.50 µg, between >0.5 µg <1 µg, concentration >1 µg,
the antibiotic is to be strongly discouraged, discouraged, antibiotic encouraged,
antibiotic strongly encouraged respectively.54
Liew et al. in 2012 evaluated PCT use for discontinuation of antibiotic with
simultaneous use of antibiotic stewardship program (ASP) in a group of patients
with malignancy. The median duration of carbapenem therapy was significantly
shorter (5 vs 7 days with p=.002). There was no significant change in mortality at
30 days.55
There are some conflicting studies which point to the contrary. Layios et al.
in their study evaluated usefulness of PCT at the time of first suspicion of sepsis.
33.8% of cases where PCT was high i.e >1 µg/L had no infection and in 14.9% of
cases when PCT was low there was an infection demonstrable.56
A romized clinical trial (RCT) by Jensen JU et al., in a Scandinavian study
(n=1200), where a PCT value of >1 ng/mL was used to monitor the incidence of
infection showed an increase in ICU days, antibiotic used, and ventilator days.57
Some limitations of PCT therapy include:
• False-positive and false-negative results
• Antimicrobial pretreatment may influence results.
• Levels of PCT may be high after trauma, surgery and cardiogenic shock.
• There is evidence to de-escalate antibiotics once PCT levels fall, but little
evidence to escalate antibiotics once PCT levels are rising.
One should avoid early aggressive adoption. It is a useful tool but should be used
with caution along with ASP clinical context of patient’s illness.
MicroRNA (miRNA)
Low sensitivity and specificity of PCT, IL-6, and CRP have prompted investigator
to search for newer more exciting biomarkers of sepsis such as miRNA, which is
also cheaper and faster. It is expressed in various body fluids and is specific for
cancer cell type, so it can be used to diagnose malignancies. Other conditions
where miRNA is being investigated is peripheral vascular disease, Alzheimer
and Parkinson’s disease. Another exciting area where miRNA holds promise is
to differentiate between Gram +ve and Gram –ve bacteremia. Circulating miRNA
in sepsis is a nascent investigative area although many confounding results
contradict these claims.
There are a number of miRNA but for prognostic and diagnostic value in
sepsis, miR-223, miR-146a, and miR-150 have shown promise. One study claims
that miR-223 cannot be used as a biomarker of sepsis as levels were not high in
healthy septic patient. Though these markers are extensively being investigated
for various disorders in human being, the ones for sepsis are still in infancy; more
research into these novel agents is required for validation as specific for sepsis.58
BIOMARKERS OF BRAIN DAMAGE AND POCD

Reported incidence of postoperative cognitive dysfunction (POCD), commonly
seen in postoperative orthopedic patient, is around 16–45%.59 Prolonged POCD
is seen in 10% cases following surgery in patients >60 years of age. It comprises
delirium, postoperative cognitive dysfunction and dementia.
For delirium to be diagnosed, following features are to be met; acute onset
of altered consciousness, visual hallucinations, anxiety with distress, and diurnal
variation of symptoms from aggression to depression. POCD symptoms vary
from mild memory loss to inability to concentrate or process information. It is
difficult to define but there are three distinct types with patient suffering from
isolated learning or memory decline, difficulty in executive function or cognitive
decline.60 Dementia is associated with irreversible pathology and presents as
global deterioration of cognitive ability but there is no clouding of consciousness.
Role of inflammation and genetic factors have been advocated in their
causation. Adrenergic response, hormones from pituitary adrenal axis, immune
and hematological changes activate cytokines and leukocytes, with release
of proinflammatory factors. Incidence of POCD after major joint arthroplasty
surgery in elderly can be as high as 72% at day six and 30% at six months.61
Some biomarkers of brain damage are:
• S100B protein
• Metalloproteinases (MMP)
• A-II spectrin breakdown products (SBDP)
Increased levels of biomarkers of brain damage in joint arthroplasty is because
of increased intramural pressure in long bones during cementing, leading to
absorption of cellular debris into systemic circulation passage into lungs. As one
third of population is having probe patent foramen ovale, debris from operative
site gains entry into brain. Emboli during cardiopulmonary bypass operation are
also a cause of POCD. Perioperative hyponatremia but not hypoxia or hypotension
causes POCD. Other risk factors proposed are age, general anesthesia,
premedicant drug like benzodiazepine. Rasmussen et al. in a randomized study
did not find a causative relationship between general anesthesia and POCD.
Regional anesthesia does not offer a beneficial effect on cognitive function. Many
studies have shown banzodiazepine does not play a role in cognitive dysfunction
after anesthesia. Similarly, studies looking into inhalational anesthetics and
POCD relationship have failed to show an association.60,62
S100B Biomarker
This marker is found mainly in Astroglial Schwann cells in brain. Increased
concentration has been found after brain infarction, toxic drugs, head trauma,
bilateral bone fracture and sepsis associated encephalopathy. Tomaszewski et al.
studied level of S100B in patients undergoing total hip arthroplasty and found
raised levels after operation, more so in cemented group than in noncemented
group. Kinoshita et al. examined S100B levels in total knee arthroplasty (TKA)
with cement use and intramedullary nailing for tibial fracture and found higher
levels in TKA cement group. The author was of opinion that this was due to
transient injury to brain by the cement.60,63,64
Metalloproteinase
Matrix metalloproteinase (MMP) was suggested as marker of blood brain barrier
dysfunction in stroke patients. Gaudet et al. found raised levels of MMP-9 in
patients who developed POCD.65
Α-II Spectrin Breakdown Product (SBDP) 145,150,120

Spectrin is a large protein composed of modular structure of α and β subunits.
It is crucial for maintaining the stability and structure of the cell membrane and
the shape of the cell. The CSF levels of SBDP are associated with neuronal injury.
In 40 adult patient with head injury, SBDP 145, 120 were raised in CSF of non-
survivors after brain injury. SBDP 145 seems to be more accurate in predicting
outcome.66
Precise etiology of POCD is not clear. Immediate postoperative delirium
prolonged POCD persisting for months or years are distinct entities. Patients at
risk of POCD should be identified before surgery, therefore, role of biomarkers of
brain dysfunction has future application.
CONCLUSION
The ideal biomarker with maximum sensitivity and specificity still eludes us.
Careful assessment of the validity of biomarkers and causes of variability is
required. They have a role to play not only in critical care setting but also in
cardiovascular diseases, cancer detection, peripheral vascular diseases, severe
trauma where post-traumatic injury stimulates an inflammatory response. The
limitations of biomarkers must be understood before using these agents in
clinical practice. PCT may not rise in presence of infection and vice versa, high
levels of BNP is also seen in noncardiogenic causes of diseases and false positive
as well as false negative results with markers are issues to be dealt with. Many
studies quoted are observational, more powered studies need to be done to
validate newer biomarkers over horizon.
KEY POINTS
• T here is uncertain relationship between serum creatinine, urine output and
pathophysiology of acute kidney injury (AKI). A number of biomarkers for AKI show
promise but need evaluation.
• Procalcitonin (PCT) should not be used aggressively. There is evidence to de-escalate
antibiotic when PCT levels are low, but there is little evidence to escalate antibiotics
when PCT values are rising.
• Low citrulline levels in plasma is a reasonable biomarker of functional enterocyte mass.
Increased plasma intestinal fatty acid binding protein (I-FABP) levels are considered to
be most accurate biomarker of acute mesenteric ischemia.
• Conventional risk factors are, at times, absent in patients with cardiovascular disease
(CVD). Role of inflammation in CVD makes identification of biomarker an emergent
need. Towards this end high sensitivity C-reactive protein (hs-CRP), BNP, troponins have
been validated. Soluble urokinase plasminogen activation receptor (suPAR) is a new
biomarker on horizon with promise.
• The incidence of postoperative cognitive disorder (POCD) increases beyond 65 years of
age. With multitude of biomarkers of brain damage in pipeline, preoperative screening
with these markers might predict the risk of this disabling condition in asymptomatic
patient in near future.
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Journal Scan
Surender K Malhotra, Krishna HM, Chand Sahai, Rakesh Kumar
JOURNAL SCAN 1
Surender K Malhotra
Effects of Volatile Anesthetics on Mortality and Postoperative Pulmonary
and Other Complications in Patients Undergoing Surgery: A Systematic
Review and Meta-analysis
Uhlig C, Bluth T, Schwarz K, Deckert S, Heinrich L, De Hert S, Landoni G, Neto AS,
Schultz MJ, Pelosi P, Schmitt J, de Abreu MG. Anesthesiology. 2016;124:1230-45.
BACKGROUND
Each year, out of about 234 million surgical procedures performed worldwide,
7 million have morbidity and 1 million have mortality.1 Most of the complications
occur due to pulmonary and other nonpulmonary causes.2 The currently used
inhalational agents like isoflurane, sevoflurane and desflurane seem to reduce
the size of myocardial infarction as well as decrease the extent of lung injury and
inflammation.3 In clinical trials too, inhalational agents have shown to be resulting
in overall organ protection, more so in cardiac surgery.4 A systematic review
and meta-analysis of randomized controlled trials was undertaken comparing
total intravenous anesthesia (TIVA) and modern inhalational agents. It was
hypothesised that postoperative pulmonary and other complications as well as
mortality is less with inhalational agents in cardiac and noncardiac surgery.
ABSTRACT
It is not established whether modern inhalational agents cause less pulmonary and
nonpulmonary complications and mortality after surgical procedures under general
anesthesia. A systematic review and meta-analysis of sixty eight randomized controlled
trials (RCTs) involving 7104 patients was undertaken. It was observed that in cardiac
surgery, there was less mortality with volatile agents (OR = 0.55; 95% CI, 0.35–0.85;
P = 0.007), less pulmonary complications (OR = 0.71; 95% CI, 0.52–0.98; P = 0.038), and
less other complications (OR = 0.74; 95% CI, 0.58–0.95; P = 0.020). In noncardiac surgery,
no reduction in mortality was seen with volatile agents (OR = 1.31; 95% CI, 0.83–2.05,
P = 0.242) nor low pulmonary complications (OR = 0.67; 95% CI, 0.42–1.05; P = 0.081) or
reduction in other complications (OR = 0.70; 95% CI, 0.46–1.05; P = 0.092) was observed. It
was concluded by the authors that in cardiac surgery, use of volatile agents as compared
to total intravenous anesthesia, resulted in less pulmonary or other complications, as well
as mortality. The similar results of reduction in mortality and pulmonary/nonpulmonary
complications were not observed after noncardiac surgical procedures. The authors have
suggested undertaking further studies to observe the effects and outcome of volatile
agents in noncardiac surgery.
Journal Scan 279
COMMENTARY
It appears to be the first review and meta-analysis of comparison between volatile
anesthetics and TIVA to observe the impact on mortality and complications
after cardiac and noncardiac surgery. Moreover, Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) guidelines have been used
that further strengthens the review and analysis.5 In total, 68 trials involving
7104 patients have been included that is an impressive number. Also, a network
meta-analysis has been incorporated to assess the contribution of individual
inhalational agent.
In case of cardiac surgery, reduced mortality with volatile agents has been
observed in an earlier analysis, too.6 This has been attributed to coronary
vasodilatation, activation of protective enzymes and translocation of cellular
key proteins.7 Moreover, volatile agents reduce inflammation in lungs, thereby
minimizing the lung injury. This anti-inflammatory effect also extends to brain,
kidneys and liver.8 In addition, volatile agents cause bronchodilatation, leading
to reduction in mechanical stress in lungs. The length of stay in cardiac surgery
patients was not affected, possibly due to protocol of minimal stay in hospital in
such procedures.
In the patients undergoing noncardiac surgery, mortality was not reduced by
volatile agents. It may be due to the fact that protective effects of volatile agents are
related to cardiac preconditioning.9 Also, the noncardiac population included could
be more heterogeneous than cardiac group. Same is the reason of lack of reduction
in pulmonary and other complications in noncardiac population. There was less
length of stay in hospital in patients receiving volatile anesthetics but only a few trials
reported hospital stay. Therefore, the noncardiac surgery population could not have
been effectively represented, and this finding should be inferred with prudence.
The practical inference of this review and meta-analysis is that volatile
anesthetics should be preferred in patients undergoing cardiac surgery, unless
there is any obvious contraindication. However, it must be kept in mind that all
kinds of cardiac surgeries have been evaluated in this analysis, though majority
of patients underwent coronary artery bypass graft surgery (CABG) surgery. In
case of noncardiac surgery population, there was higher mortality with volatile
anesthetics that may be attributed to selection of high risk of patients. To assess
the organ protecting properties of volatile agents, large randomized controlled
trial (RCTs) are required in noncardiac surgeries to evaluate pulmonary and
other complications.
In the present meta-analysis, there are a few limitations, too. For example,
the assessment of trials heterogeneous and risk of bias is large. The majority
of the trials were small and number of events reported, too was limited that
could jeopardize the predictability of mortality. Nevertheless, the authors made
adjustment for the effect size with respect to small sample size and Peto odds ratio
method was used that provides more accurate statistical analysis for rare events.10
The authors used network meta-analysis in all trials, irrespective of number of
trials. The publications included in this review covered a period of three decades.
The advancements in postoperative care could have influenced the results. The
publication bias may also influence the evaluation since the studies with negative
results are less likely to be published. The pulmonary and other complications
were included irrespective of their severity. For instance, atelectasis and ARDS
were included in the same manner. The postoperative complications largely
depend on the kind and extent of surgery which may affect the role of anesthetic
agents.11 Likewise, in cardiac surgery population, CABG, valve surgery, with or
without pump procedures, have been counted together though most patients
underwent CABG. Such generalization of cardiac surgeries is not appropriate.
There is no mention of use of opioids in this meta-analysis that could have
added up to cardiac protection.12 The mortality rates were comparatively less
in cardiac surgery, probably due to sampling bias of small trials and employing
narrow inclusion criteria that could have lead to inclusion of mostly low- and
medium-risk surgical procedures.
The authors have concluded that in cardiac surgery general anesthesia with
volatile anesthetics as compared to TIVA provides better outcome in the form of
reduced mortality and lesser pulmonary and other complications. Such benefits
were not as substantial in noncardiac surgery. Hence, more studies are required
in noncardiac surgery to further assess the effects and outcome of volatile
anesthetics.
REFERENCES
1. Weiser TG, Regenbogen SE, Thompson KD, Haynes AB, Lipsitz SR, Berry WR, et al. An
estimation of the global volume of surgery: A modelling strategy based on available
data. Lancet. 2008;372:139-44.
2. Pearse RM, Moreno RP, Bauer P, Pelosi P, Metnitz P, Spies C, Vallet B, Vincent JL, Hoeft
A, et al. European Surgical Outcomes Study (EuSOS) Group for the Trials Groups
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Anaesthesiology: Mortality after surgery in Europe: A 7 day cohort study. Lancet. 2012;
380:1059-65.
3. Fortis S, Spieth PM, Lu WY, Parotto M, Haitsma JJ, Slutsky AS, Zhong N, Mazer CD,
Zhang H. Effects of anesthetic regimes on inflammatory responses in a rat model of
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4. De Hert S, Vlasselaers D, Barbé R, Ory JP, Dekegel D, Donnadonni R, Demeere JL, Mulier
J, Wouters P. A comparison of volatile and non volatile agents for cardioprotection
during on-pump coronary surgery. Anaesthesia. 2009;64:953-60.
5. Moher D, Liberati A, Tetzlaff J, et al; PRISMA Group: P referred reporting items for
systematic reviews and metaanalyses: The PRISMA statement. BMJ. 2009;339:b2535.
6. Landoni G, Greco T, Biondi-Zoccai G, Nigro Neto C, Febres D, Pintaudi M, Pasin L,
Cabrini L, Finco G, et al. Anesthetic and survival: A Bayesian network meta analysis of
randomized trials in cardiac surgery. Br J Anaesth. 2013;111:886-96.
7. Liu KX, Xia Z. Potential synergy of antioxidant N-acetylcysteine and insulin in restoring
sevoflurane postconditioning cardioprotection in diabetes. Anesthesiology. 2012;
116:488-9; author reply 489-90.
8. Kim M, Park SW, Kim M, et al. Isoflurane activates intestinal sphingosine kinase to
protect against bilateral nephrectomy-induced liver and intestine dysfunction. Am J
Physiol Renal Physiol. 2011;300:F167-76.
9. Lee HT, Chen SW, Doetschman TC, Deng C, D’Agati VD, Kim M. Sevoflurane protects
against renal ischemia and reperfusion injury in mice via the transforming growth
factor-β1 pathway. Am J Physiol Renal Physiol. 2008;295:F128-36.
10. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective
studies of disease. J Natl Cancer Inst. 1959;22:719-48.
11. Mazo V, Sabaté S, Canet J, Gallart L, Gama de Abreu M, Belda J, Langeron O, Hoeft
A, Pelosi P. Prospective external validation of a predictive score for postoperative
pulmonary complications. Anesthesiology. 2014;121:219-31.
12. Zaugg M, Lucchinetti E, Spahn DR, Pasch T, Garcia C, Schaub MC. Differential effects of
anesthetics on mitochondrial K (ATP) channel activity and cardiomyocyte protection.
Journal Scan 281
JOURNAL SCAN 2
HM Krishna
Microbiological Contamination of Drugs during Their Administration for
Anesthesia in the Operating Room
Gargiulo DA, Mitchell SJ, Sheridan J, Short TG, Swift S, Torrie J, Webster CS, Merry AF,
BACKGROUND
Is anesthesiologist a potential source for perioperative infections? This question
is being posed by some of our colleagues from surgical specialities. The
positive outcome of this doubt is the surge of studies evaluating the practice of
anesthesiologists that can increase or decrease the likelihood of perioperative
infections. This awareness is also leading to a slow albeit definite changes in the
practice of anesthesiologists. The present study evaluates whether bolus injection
of drugs by anesthesiologists poses the threat of injection of potentially harmful
microbes into patients’ circulation.1
ABSTRACT
In this prospective audit of 303 patients, bolus injections of drugs (except propofol and
antibiotics) were done through a 0.2 µm filter. The flushed content from these filters
and the residual drug in the syringes used to load the drugs were cultured at the end
of the anesthetic. The ease of using the filter was also reported. Microorganisms were
isolated from 6.3% of filter units (19 filters out of the 300 cases). Isolated organisms were
Staphylococcus capitis, Staphylococcus warneri, Staphylococcus epidermidis, Staphylococcus
haemolyticus, Micrococcus luteus/lylae, Corynebacterium, and Bacillus species. 2.4% of
syringes with residual drug (55 out of 2318 syringes) grew organisms Kocuria kristinae,
Staphylococcus aureus, and Staphylococcus hominis in addition to the above mentioned
organisms. The authors concluded that potentially infectious microorganisms are being
injected into patients during bolus intravenous injections by anesthesiologists.
COMMENTARY
Preventing perioperative infections in a patient is a collective effort by all the
personnel involved in patient care during the perioperative period.2 Instead of
playing the blame game we should work together to improve our practices that can
minimize the incidence of perioperative infections. Implementation of bundled
care against ventilator associated pneumonia (VAP), sepsis, hand hygiene
practice illustrate our movement in the right direction.3 But can something as
subtle as injecting a drug intravenously pose a threat of infection to the patient?
This study seeks to find an answer to this question.
The entire study is formulated on the findings of a simulated study where
microorganisms could be isolated from 13% of collected injectate during simulated
anesthetic injections.4 Ideally all drugs are to be drawn and administered by
the anesthesiologist with aseptic precautions. But considering the turnover of
the modern day operating rooms, logistic availabilities and the attitudes of the
anesthesiologists does this ideal turn into practice?
In this study conducted at 19 operating rooms of a tertiary teaching hospital at

New Zealand the authors do not mention what exactly was the ‘aseptic practice’
followed in drawing up and administering the drugs. So we have no clue about
the standard practice of drawing the drugs and injection and to what extent it was
adhered to.
The method of quantifying the microorganisms trapped in the filter is
innovative. Since there was no way by which the filter membranes could be
extracted out from the filters the authors devised their ingenious technique of
backflushing the filters to extract the trapped microbes in the filters. This new
technique was not just arbitrarily applied in the study. It was validated by the
laboratory experiment which confirmed that backflushing could successfully
extract the trapped microbes from the filters.
Could repeated flush with 0.9% sodium chloride been one of the causes for
the microbial contamination (since 0.9% sodium chloride appears repeatedly in
Table 3 of the said paper)? This flush had to be done in this study every time
the drug was injected through the filter assembly. Repeated connections and
disconnections of syringes at stop cocks does provide more chance for infection.
It is not clear whether the findings of this audit from one hospital can be
generalized to all settings especially since the authors have not mentioned the
aseptic protocol followed in their hospital to load and administer the drugs.
Nevertheless it makes us introspect our hand hygiene practices.5 Aseptic
precautions are not taken widely in our country to load the drugs and inject
them to the patients (exception being for the immunocompromised patients).
Hand hygiene precautions and clean gloves are strongly desirable. Till the
clinical translation of the findings of this study becomes clear (i.e. does microbial
injection result in increased incidence of infection?) one cannot recommend
that strict aseptic precautions be taken while loading and injecting the drugs to
an immunocompetent patient. But the findings should warn us to use simple
measures like use of hand rub antiseptic solution every time before and after
loading the drug and injecting the drug. Cleaning the bung of the vial with
alcohol swab, limiting the use of number of withdrawals from a vial could be
other effective measures.
Does this study provide a strong justification to use microbial filters at the
intravenous injection port? Not necessarily because the presence of microbes
need not mean presence of infection. Only a study comparing the incidence
of infection (and not just extraction of microbes) with and without the use of
filters can answer this. It may be interesting to find out if standardized and strict
protocolled technique of loading and administering the drugs can reduce the
incidence of microbial contamination of drugs.
REFERENCES
1. Gargiulo DA, Mitchell SJ, Sheridan J, Short TG, Swift S, Torrie J, et al. Microbiological
contamination of drugs during their administration for anesthesia in the operating
room. Anesthesiology. 2016;124:785-94.
2. World Health Organization: The Burden of Endemic Health Care-associated Infection
Worldwide. Geneva, World Health Organization, 2011. Available at: http://www.who.
int/gpsc/country_work/burden_hcai/en/
3. Loftus RW, Muffly MK, Brown JR, Beach ML, Koff MD, Corwin HL, Surgenor SD,
Kirkland KB, Yeager MP. Hand contamination of anesthesia providers is an important
risk factor for intraoperative bacterial transmission. Anesth Analg. 2011;112:98-105.
Journal Scan 283
4. Gargiulo DA, Sheridan J, Webster CS, Swift S, Torrie J, Weller J, Henderson K, Hannam
J, Merry AF. Anaesthetic drug administration as a potential contributor to healthcare-
associated infections: A prospective simulation-based evaluation of aseptic techniques
in the administration of anaesthetic drugs. BMJ Qual Saf. 2012;21:826-34.
5. Fernandez PG, Loftus RW, Dodds TM, Koff MD, Reddy S, Heard SO, Beach ML, Yeager
MP, Brown JR. Hand hygiene knowledge and perceptions among anesthesia providers.
Anesth Analg. 2015;120:837-43.
JOURNAL SCAN 3
Chand Sahai
Use of direct oral anticoagulants with regional anesthesia in orthopedic
patients.
Cappelleri G, Fanelli A. Journal of Clinical Anesthesia. 2016;32:224-35.
BACKGROUND
One of the major contributors to mortality, morbidity and healthcare expenses
is venous thromboembolism (VTE) especially in the elderly patients undergoing
major orthopedic procedures like replacement arthroplasty. Perioperative
thromboprophylaxis with anticoagulants is the norm in such cases. These
procedures are usually carried out under neuraxial anesthesia, extended
postoperatively for pain relief, thus exposing patients to the risk of spinal and
epidural hematoma. The newer direct oral anticoagulants (DOACs) are approved
in the USA and European Union for VTE prophylaxis. The article reviews current
literature, guidelines and best practice in the scenario of VTE prevention in major
orthopedic surgery.
ABSTRACT
The direct oral anticoagulants (DOAC) apixaban, rivaroxaban and dabigatran are of
late being used for VTE prophylaxis. DOACs have the advantage of a short onset of
action and are usually started 1–24 hours postoperatively after assuring hemostasis.
Even though the risk of spinal or epidural hematoma is relatively small in patients on
DOAC it is nevertheless to be taken into consideration since the consequences of spinal
cord compression are devastating. It is vital to understand their pharmacology to plan
discontinuation and restarting of the drug. This article examines the current literature,
guidelines and best practice weighing the risks and benefits of direct oral anticoagulants
and regional anesthesia in patients undergoing major orthopedic surgery, including
those with renal impairment or chances of heavy bleeding.
COMMENTARY
Major orthopedic surgery including total hip replacement (THR), total knee
replacement (TKR) and hip fracture surgery carries a high risk of venous
thromboembolism (VTE). A variety of strategies to prevent VTE are available
including the use of mechanical compression devices and/or pharmacological
agents including aspirin, LMWH and the recently introduced direct oral
anticoagulants.
Orthopedicians are concerned that pharmacological VTE prophylaxis could
lead to postoperative bleeding, hematoma formation and thence to prosthetic
joint infection which would need re-exploration and even removal of the
prosthesis. The anesthesiologists are apprehensive about the risk of a spinal or
epidural hematoma with devastating effects.
The majority of patients for major orthopedic surgery are elderly, who are
at risk of VTE. Moreover, postoperative pain is severe enough to interfere with
optimum rehabilitation and mobility thus increasing the risk of thromboembolic
events. Consequently a balance has to be struck so that at the time of surgery
Journal Scan 285
there is little or no anticoagulant effect meanwhile ensuring the shortest possible

time to restart the antithrombotic treatment.
Several clinical guidelines have been devised regarding perioperative VTE
prophylaxis on the basis of available medical literature or the consensus of
experts in the field. Orthopedic surgeons refer to 3 clinical guidelines dealing
with prophylaxis of VTE; from the American College of Chest Physicians (ACCP),
from the Surgical Care Improvement Project (SCIP), and those from the American
Academy of Orthopedic Surgeons (AAOS). They have voiced concerns over the
ACCP guidelines which emphasize pharmacologic prophylaxis, believing that
these guidelines underestimate the danger of bleeding complications and other
unfavorable outcomes, such as long-lasting wound drainage or deep infection,
associated with the use of anticoagulants.
Anesthesiologists follow guidelines by ASRA, ESA or other regional guidelines,
regarding perioperative management of patients a propos preoperative
interruption and restarting the anticoagulant postoperatively, based on clinical
experience and the elimination half-life of the anticoagulant used. The ESA
guidelines recommend extreme caution while using rivaroxaban along with
neuraxial block, while ASRA are still evaluating dabigatran and rivaroxaban.
No guideline provides detailed information on the management of patients on
direct oral anticoagulants. Moreover, published evidence does not establish
whether these prophylactic strategies affect rates of all-cause mortality, fatal PE,
symptomatic PE, or symptomatic DVT in patients undergoing elective hip or knee
arthroplasty. Clinical guidelines are not the last word in patient care and are open
to question and cannot be replaced by clinical acumen. The ACCP guidelines
were based on the development of DVT (diagnosed using ultrasonography
or venography) as a primary measure. DVT however did not always lead to
pulmonary embolism (PE).
When a drug is stopped, its lessening in the circulation is dependent upon its
half-life: 50% after one half-life till 1.6% is left after 6 half lives. It is recommended
to wait for 2 half lives of the anticoagulant to reduce the bioavailability of the
drug to <25%. However, as the authors point out, the guidelines do not take into
consideration the profile of patients who present for arthroplasty surgeries. In
the elderly especially in those with comorbidities affecting renal functions, it is
better to wait for 3–5 half lives before giving regional anesthesia. The authors
recommend thorough monitoring of the coagulation including measuring the
concentration of the anticoagulant in the blood.
A 2013 editorial1 mentions that hematomas after epidurals were thought to be
uncommon before the advent of routine thromboprophylaxis and entry of various
antithrombotic agents. Though the overall incidence was low without traumatic
puncture or in those not on heparin or aspirin, the rate increases if there were risk
factors present. These factors include elderly patients, females, coagulopathies,
spinal abnormalities, drug and procedure related among others.
The article under consideration goes into great detail about the three DOACs:
dabigatran, rivaroxaban and apixaban: when to stop before procedure, how to
test for residual effect, metabolism, elimination, half-life and when to restart
DOAC in the postoperative period. Dabigatran a direct thrombin inhibitor,
dispensed as a prodrug dabigatran etexilate is hydrolyzed by gastric esterases to
active drug. Its pharmacokinetics makes for a predictable drug action and very
little drug interactions. It is contraindicated in patients with creatinine clearance

<30 mLkg–1. Rivaroxaban is a factor Xa inhibitor, with a rapid onset of action and
peak plasma concentrations within 2.5–4 hours. Its clearance is affected by renal
disease and should also be avoided in patients with moderate to severe hepatic
dysfunction. Lastly, apixaban is a highly specific factor Xa inhibitor. Its peak levels
are attained in 1–2 hours and it has multiple routes of elimination.2
Unfortunately the guidelines from ASRA, ESA or SSAI differ in the time
intervals and this is somewhat perplexing. Douketis has written a piece titled
‘Daring Discourse’, which is a critique of the 2015 ASRA Guidelines. According to
these DOACs need to be stopped 4–6 days for dabigatran; 3 days for rivaroxaban
and 3–5 days for apixaban. Resumption of DOACs to be done after 24 hours.
This interruption allows 5 elimination half-lives of the drugs and~3% residual
anticoagulant effect. The contention by Douketis and colleagues3 is that the
guidelines have not been backed by evidence, which has been admitted in the
said guidelines, so it would have been more appropriate to have labeled them
as clinical guidance, since high standard evidence is not available. They also
mention an unpublished study by them on patients on dabigatran, using a
standardized preprocedure protocol: stopping drug for 24 hours or more if
bleeding risk was low and 48 hours or more if high risk of bleeding and tested
the residual anticoagulant effect when surgery was carried out, using tests such
as aPTT, TT and dTT which is most sensitive to dabigatran. They concluded that
a longer waiting period is required for high risk of bleeding procedures so that
>95% of patients would have no detectable residual effect of the DOAC.
The authors also discuss various risk factors for the development of post-
regional anesthesia complications like postdural puncture headache, backache,
peripheral nerve injuries and the most dreaded spinal and epidural hematoma.
They also examine alternatives to neuraxial blocks such as peripheral nerve
blocks, but here too there is a paucity of solid evidence on which to base
recommendations for the employment of a particular peripheral nerve block, and
lacking clarity on the potential neurological deficit when there is a hematoma in
a noncompressible site and both ESA and ASRA guidelines have suggested that
anesthesia choice should also include deeper peripheral nerve blocks.
All in all a fairly comprehensive article that has encompassed the progression
made in combining anticoagulants and timing of neuraxial blocks, a tightrope
walk between bleeding and thromboembolic events, patient characteristics
and comorbidity. All of which serves to emphasize that one size does not fit all,
and each case deserves individual attention to detail and altering anesthetic
management so that safety is paramount.
REFERENCES
1. Horlocker T, Kopp S. Epidural Hematoma After Epidural Blockade in the United States:
It’s Not Just Low Molecular Heparin Following Orthopedic Surgery Anymore. Anesth
Analg. 2013;116:1195-7.
2. Benzon HT, Avram MJ, Green D, et al. New oral anticoagulants and regional anaesthesia.
Br J Anaesth. 2013;111(S1):i96-i113.
3. Douketis D, Syed S, Schulman S. Periprocedural Management of Direct Oral
Anticoagulants. Comment on the 2015 American Society of Regional Anesthesia and
Pain Medicine Guidelines. Reg Anesth Pain Med. 2016;41:127-9.
Journal Scan 287
JOURNAL SCAN 4
Rakesh Kumar
The Physiology of Cardiopulmonary Resuscitation
Lurie KG, Nemergut EC, Yannopoulos D, Sweeney M. Anesth Analg. 2016;122:767-83.
BACKGROUND
This E-Review Article comes from authors representing Emergency Medicine,
Internal Medicine, Anesthesiology, Neurological Surgery and Pediatrics
departments and having a huge amount of research in the field of CPR. It mainly
discusses the impact of regulating the intra-thoracic pressure during CPR while
underlining the importance of a correctly performed high-quality standard CPR
(S-CPR). Both Lurie and Sweeney are co-inventors of the impedance threshold
device (ITD) and Lurie is also the co-inventor of the active compression
decompression CPR (ACD-CPR) device (both used to regulate intra-thoracic
pressure). Although this makes them the ideal people to write this review article,
the readers should also be aware of this fact while interpreting the article.
ABSTRACT
Many changes occur during the compression and decompression phases of chest
compression and during ventilation while performing the standard CPR (S-CPR). Through
a discussion of these changes, this article highlights the common mistakes during S-CPR
and the importance of sticking to the most recent resuscitation guidelines. Thereafter
it discusses the extrapolation of physiological understanding of CPR in incorporating
some new strategies like intra-thoracic pressure regulation techniques, head-up position
during CPR and “postconditioning” in improving outcomes of CPR attempts. Finally it
touches upon the concept of Resuscitation Bundle that amalgamates multiple strategies
to improve CPR outcomes even more. And all through, it underscores the importance of
high quality CPR to reap the benefits of these exciting new discoveries.
COMMENTARY
The physiologic principles that underlie the life-saving process of cardiopulmonary
resuscitation (CPR) still remain only partially understood and are often
controversial. Some of the questions also remain unanswered, such as: (i) How to
ensure a greater blood flow than the minimal amount produced by conventional
closed chest cardiac massage; (ii) What tools can help provide better quality CPR;
(iii) How to reduce the potential for brain injury associated with the simultaneous
arterial and venous pressure compression waves focused toward the brain each
time the chest is compressed; (iv) How to prevent reperfusion injury in the first
seconds and minutes of reperfusion, especially after prolonged periods of no
flow; and (v) How to improve the postresuscitation care. No wonder then that the
overall survival rates have hovered around 7% for out-of-hospital cardiac arrest
and <30% for in-hospital cardiac arrest in USA.1 However, over the past 20 years,
a greater understanding of heart–brain–lung interactions has resulted in novel
resuscitation methods and technologies that significantly improve outcomes
from cardiac arrest. Taken together, these new approaches provide an innovative,
physiologically based pathway to increase survival and quality of life after cardiac
arrest. The review tries to highlight some recent advances in resuscitation science
aimed at addressing first four of the five unanswered questions above.
Although the article does not quote the most recent AHA guidelines,2 but
the features of perfectly performed S-CPR mentioned are similar to the ones in
these guidelines, i.e. compression depth of at least 5 cm and rate of 100–120 bpm,
allowing complete recoil and by avoiding any leaning during the decompression
phase, thereby enhancing cardiac refilling, minimizing interruptions in chest
compression as much as possible and avoiding hyper- or hypoventilation.
However, even when performed perfectly, S-CPR itself provides only 15% to
25% of normal cardiac output. Understanding some of the limitations of S-CPR
has resulted in several discoveries that hold promise of significantly enhancing
cardiocerebral circulation during cardiac arrest. Studies on CPR physiology have
resulted in several fundamentally new approaches to improve outcomes after
cardiac arrest. These include ways to harness the thoracic pump to enhance
circulation to the heart and brain by transforming the thorax into an active
pump to circulate more blood. The newly appreciated concept of intrathoracic
pressure regulation (IPR) has resulted in innovative technologies and approaches
to enhance perfusion, decrease ICP, and improve cardiac arrest outcomes.
Additional discoveries associated with cardiac arrest include ways to reduce the
potential for reperfusion injury, new insight into the potential importance of the
position of the head during CPR, and methods to improve postresuscitation care.
Essential for all of these potential advances is the need for the delivery of high-
quality CPR in accordance to AHA guidelines.
Intrathoracic Pressure Regulation Therapy

The concept of IPR is embodied in a number of noninvasive devices developed
to regulate changes in intrathoracic pressure and to provide greater circulatory
support than can be generated by S-CPR itself. These include Active Compression
Decompression CPR (ACD CPR) and Impedance Threshold Device (ITD). In
ACD CPR, intrathoracic pressures increase and decrease by repetitively pulling
upward and pushing downward on the chest with a suction device, promoting
greater ventilation and circulation than with S-CPR. Further study of ACD CPR
resulted in a discovery of the inspiratory ITD. By transiently impeding airflow into
the lungs during the chest wall recoil or decompression phase of CPR, use of the
ITD results in a significant reduction in intrathoracic pressure during S-CPR and
ACD CPR. By this means, the ITD significantly augments blood flow to the heart
and brain during S-CPR, ACD CPR, and when used during CPR with automated
devices.
The largest human trial, the National Institutes of Health Resuscitation
Outcomes Consortium (ROC) Prehospital Resuscitation Impedance Valve and
Early Versus Delayed Analysis (PRIMED) study compared a sham versus active
ITD and early versus late analysis and defibrillation. The investigators reported
no benefit of the ITD.3 However, on closer scrutiny and repeat analysis and
independent re-analysis of the ROC PRIMED study data, it was discovered that
there was a significant benefit of ITD in patient receiving high quality S-CPR in
accordance to the AHA Guidelines but not in those where the S-CPR was of poor
quality, thus underscoring the importance of high quality S-CPR even for reaping
the benefits of the advanced techniques!
Journal Scan 289
Advanced Intrathoracic Pressure Regulation

A series of devices have been designed to harness the changes in intrathoracic
pressure to enhance venous return to the heart and circulate more blood to the
brain and heart. They work by actively withdrawing the respiratory gases from
the lungs to generate negative intrathoracic pressure during the entire expiratory
phase after a positive pressure breath. When this approach is combined with
S-CPR or ACD CPR, blood flow to the heart and brain is enhanced. A device that
provides this kind of IPR therapy, called the intrathoracic pressure regulator
device (ITPR), has been approved for use in hypotensive patients by the Food
and Drug Administration to enhance circulatory adequacy. In animals, brain
blood flow is increased by approximately 50% with ACD + ITPR versus ACD +
ITD. In humans, the use of S-CPR plus the ITPR significantly enhances circulation
as measured by ETCO2 during CPR and significantly increases the likelihood of
successful resuscitation from 46% to 73%. However, research with this new
approach is in its infancy.
Head-Up CPR
Recent animal (pigs) studies on the position of the head and body during CPR have
demonstrated that elevation of the head during CPR has a profound beneficial
effect on intracranial pressure (ICP), cerebral perfusion pressure (CerPP), and
brain blood flow when compared with the traditional supine horizontal position.
However, these benefits are realized only when an ITD is present; when the ITD
is removed from the airway in these studies, systolic blood pressure and coronary
and CerPP decrease rapidly, and currently clinical studies are lacking.
Reperfusion Injury Protection

In a general sense, this concept also known as “postconditioning” can be defined
as brief periods of reperfusion alternating with intentional reocclusion applied
during the first minutes of reperfusion. There are multiple ways to reduce or prevent
reperfusion injury based on the putative mechanisms of action, which include
ischemic postconditioning with intentional short periods of no flow after reflow
(Stutter ACD CPR + ITD), and pharmacologic agents, which activate reperfusion
injury salvage kinase pathways or inhibit the opening of mitochondrial
permeability transition pores. More recent studies suggest that with reperfusion
injury protection, the brain may be able to survive for well >15 minutes in the
absence of any perfusion. Bartos et al.4 used multiple simultaneous interventions
hypothesized to improve flow, reduce reperfusion injury, and accelerate cellular
and vital organ recovery. Enhanced flow was provided with ACD + ITD CPR.
Postconditioning was provided by 3 short intentional 20-second pauses in CPR
and administration of sevoflurane to preserve mitochondrial respiration after
prolonged ischemia and reperfusion, and a synthetic surfactant, poloxamer 188
was administered to help seal nanosized holes in and between cells. The authors
found that more than half of the animals treated with this unique bundle were
awake, alert, and functionally normal 48 hours after cardiac arrest while none of
the control animals survived.4 Clinical studies are now needed to determine the
potential added value of reperfusion injury protection after prolonged untreated
cardiac arrest.
Table 1 Potential ways to improve outcome during CPR

Optimize Minimize cell Restore Optimize Minimize
perfusion permeability B-B barrier intracellular postresuscitation
metabolism injury cascades
CPR devices X X
Head position X X X
Postconditioning X X X
Synthetic X X X
surfactants
Abbreviation: CPR, Cardiopulmonary resuscitation.
The Resuscitation Bundle

Multiple treatments (the collection can be called Resuscitation Bundle) are
needed for success in the chain-of-survival approach to the treatment of cardiac
arrest. The most effective resuscitation bundles to date include efforts to promote
widespread use of bystander CPR, public access defibrillation, high quality CPR
by first responders and advanced life support providers, use of adjuncts that
lower negative intrathoracic pressure during the decompression phase of CPR,
and strategies that include postresuscitation revascularization and therapeutic
hypothermia, or at least the prevention of fever. Currently, the bundled approach
to prehospital care has significantly improved survival with good neurological
function for all patients to as high as 20% in some cities and counties.
Clinical Implications and the Future

The authors rue the fact that even after over half a century, we remain in our
infancy in understanding the complex physiology of cardiac arrest and CPR. They
feel that consistent and definitive advances in the treatment of cardiac arrest will
require the synergy between already established and multiple relatively new
interventions (Table 1), none of which is exceptionally difficult to implement,
in a bundle-of-care approach to this multifactorial disease state. The authors
anticipate that once many of these newer modalities have been scientifically
verified and combined with current system-based approach to care, the potential
to successfully and fully resuscitate many patients who we cannot help with
current management will be well within our reach.
REFERENCES
1. Bardy GH. A critic’s assessment of our approach to cardiac arrest. N Engl J Med.
2011;364:374-5.
2. AHA Advanced Cardiovascular Life Support, Provider Manual, 2016.
3. Aufderheide TP, Nichol G, Rea TD, Brown SP, Leroux BG, Pepe PE, Kudenchuk
PJ, Christenson J, Daya MR, et al. Resuscitation Outcomes Consortium (ROC)
Investigators. A trial of an impedance threshold device in out-of-hospital cardiac
arrest. N Engl J Med. 2011;365:798-806.
4. Bartos JA, Matsuura TR, Sarraf M, Youngquist ST, McKnite SH, Rees JN, Sloper DT,
Bates FS, Segal N, et al. Bundled postconditioning therapies improve hemodynamics
and neurologic recovery after 17 min of untreated cardiac arrest. Resuscitation.
2015;87:7-13.
Index
Page numbers followed by f refer to figure and t refer to table
A Antibiotic
prophylaxis 156
Acid-base disorders 199
stewardship program 271
Adenotonsillectomy 145
Anticoagulant therapy 236
Adenylate cyclase activity 176
Antioxidants 5
Adrenalectomy, laparoscopic 117
Antiplatelet therapy 236
Adult respiratory distress syndrome 210
Antiseizures prophylaxis 204
Aintree intubation catheter 189
Antithyroid drugs 171
Airway 125
Anxiolysis 98
assessment 186
Appendages 69
management 186, 188
Arachidonic acid 5
Alcohol 171
Arginine 3
intoxication 201
Artery
Alpha linolenic acid 5
disease, coronary 265
American Academy of Orthopedic
femoral 35f
Surgeons 285
subclavian 28f
American College of Chest Physicians 285
Atherosclerosis 265
American Heart Association 256, 265
Atrial fibrillation, postoperative 258
American Society of Anesthesiologists
Axillary artery 26f, 29f
Closed Claim Project 14, 16
American Society of Anesthesiologists
Practice Guidelines 191
B
American Society of Enteral Nutrition 2 Bariatric surgeries, laparoscopic 98
Amino acid glutamine 4 Basic airway management techniques 187
Analgesia 117, 203 Benumof’s airway 193
neuraxial 96 Benzodiazepines 171
postoperative 159 Beta blockade, perioperative 254, 255
systemic 48 Biotrauma 212
Anaphylaxis 137 Blood transfusion 136
perioperative 121 Brachial plexus
prevention of 126 cords of 29f
Androgens 171 divisions of 28f
Anemia 154, 199, 266 Brain
Anesthesia 12, 97, 132, 137, 231 damage, biomarkers of 272
care 98 trauma foundation 199
legal aspects of 13 B-type natriuretic peptide 266
management 193 Buprenorphine 72, 73
minimum monitoring standards of 18
ophthalmic 236 C
pediatric 98 Calcitonin gene-related peptide 83
regional 16, 25, 50, 136 Calcium channel blockers 109
technique 157 Cannula technique 191
total intravenous 96, 278 Carbamazepine 171
Anesthetics Cardiac risk index, revised 257
inhalational 166 Cardiopulmonary resuscitation 287, 290
intravenous 167 Cardiovascular
Angiotensin converting enzyme disease study 265
inhibitor 171 system, biomarkers of 265
Catechol-O-methyltransferase 107, 178 European North American Study of

Central nervous system 59, 82, 170 Severity Systems 60
Cerebral perfusion pressure 200, 289 European Society of Intensive Care
Cerebrospinal fluid 245 Medicine 59
Cervical spine 186
Chlorhexidine 124 F
Cholecystokinin 177 Facial
Citrulline levels 270 expression 43
Cocaine 171 fractures 184t
Cognitive dysfunction Faciomaxillary trauma 193f
postoperative 243, 272 anesthetic management of 184
Color graded scale 42, 43 Fatty acid
Consumer Protection Act 22 arachidonic acid 5
Continuous positive airway pressure 232 binding protein 270
Corynebacterium 281 Fentanyl 72, 73
Cranial nerve Fever 199
injuries 249 Fluid resuscitation, intravenous 126
palsies 250
C-reactive protein 265 G
Cricothyroidotomy 191
C-spine injury 192 Gamma linolenic acid 5
Cushing’s ulcers 205 Gastrointestinal tract 1, 205
Gland, handling of 114
D Glasgow Coma Scale 55, 59, 63, 200
Glomerular filtration rate 166, 268
Deep venous thrombosis prophylaxis 204 Glutamine 3, 4
Delirium 242, 272 Gluteus maximus muscle 36
Dementia 272 Glycemic control, postoperative 159
Dermis 69 Gut failure, biomarkers of 269
Desflurane 171
Dexmedetomidine 93, 98 H
Diabetes insipidus 205 Head injury 186
Diazepam 171 Headache 201
Diclofenac 48, 49 Heart
Diclofenac epolamine 72 disease, cardiovascular 265
Diethylstilbestrol 171 failure, congestive 104
Direct oral anticoagulants 284 Hematoma, extradural 205
Docosahexaenoic acid 5 Hemorrhage
Dorsal root ganglia 82 management of 192
Drug intoxication 201 severe intracranial 204
subarachnoid 266
E Hip fracture surgery 284
Edema, origin of 210 Hybrid patches 71
Eicosapentaenoic acid 5 Hyperalgesia, opioids induced 174
Emergency airway management 192 Hyperglycemia 132
Endocrine disorders 205 Hypertension 103
Endogenous opioid ligands 85 pathophysiology of 105
Endoscopic sinus surgery, functional 94 pregnancy induced 167
Endotracheal tube 232 Hypertonic saline 204
End-stage renal disease 63, 266 resuscitation 203
Enflurane 171 Hypocapnia 199
Enteral nutrition 1 Hyponatremia 199
Epidermis 69 Hypo-osmolality 199
Epinephrine 125 Hypotension 199
Index 293
Hypothermia 132 Lidocaine 72

prevention of 158 Lignocaine 72, 171
Hypoxemia 199 patch 75
Liposomes 78
I Lithium 171
Ibuprofen 48, 49 Local anesthetics, eutectic mixture of 75
Illness scoring systems, severity of 53 Logistic organ dysfunction score 53, 54, 60
Immune cells 85, 86 Low molecular weight heparin 156
Immunity 132 Lower face fractures 185
acquired 131 Lumbar plexus 33
innate 131 block 34
nonspecific 131 Lumen laryngeal devices 190
specific 131 Lung injury
Immunonutrition 2 acute 5
Incidentaloma 105, 105t ventilator induced 210, 211
Inflammation, modulation of 86 Lung protective ventilation 212
Infraglottic airway devices 191 Lymphoid tissue 1
Injury
primary 199 M
severity score 63 Matrix metalloproteinase 273
Inspiratory occlusion method 216 Maxillofacial trauma 184, 192
Intensive care unit 2, 63, 93, 199 Maxillomandibular fracture 187f
Intercellular adhesion molecule-1 86 Medicolegal issues 12
Interleukin–18 267 Meperidine 171
Intestinal-fatty acid binding protein 270 Merkel cell 69
Intracellular cyclic adenosine mono Meta iodo benzyl guanidine 107
phosphate 176 Metalloproteinase 272, 273
Intracranial pressure 200, 289 Micrococcus luteus/lylae 281
monitoring 202 Midazolam 171
Intrathoracic pressure regulation 288 Mid-face fractures 185
advanced 289 Mortality
therapy 288 prediction model 58
Iontophoresis 76 probability model 53
Ischemic optic neuropathy Multi-organ failure 269
anterior 244 Multiple endocrine neoplasia 106
posterior 244 Multiple organ dysfunction score 53, 59, 60
Myocardial infarction 254, 255
K acute 254
Keratinocytes 69
Ketamine 134 N
Ketorolac 49 Narcotic drugs 227
Kidney injury National Institute of Health Biomarkers
acute 274 Definition Working Group 264
molecule-1 267 Natural killer cell 134
Nausea 158
L vomiting, postoperative 95
Langerhans cell 69 Neonatal intensive care 231
Laryngeal mask airway 190, 194 Nerve block
Laryngoscopes, fiberoptic 190 femoral 34
Laryngotracheal injury 192 iliohypogastric 31
Laser therapy 231 Nerve
Lateral femoral cutaneous nerve 33 blocks 47t
LeFort fractures 185f femoral 33, 35f
injuries, perioperative 250 Paraganglioma 104f

radial 26f Pediatric objective pain scale 44
Neural blockade, perioperative 96 Peptides beta-endorphin 85
Neuraxial anesthesia, complications of 248 Perianesthesia stressors 132
Neuromuscular blockers 168, 171 Perioperative ischemic evaluation trial 255
Neuronal apoptosis, opioids induced 178 Peripheral opioid receptors 82, 83, 86
Neutrophil gelatinase-associated Persistent anterograde amnesia 201
lipocalin 267 Pharmaconutrition 2, 3
Nitric oxide 270 Phenytoin 171
synthase 3 Pheochromocytoma 103, 104f, 106, 107,
Noncommunicable diseases 227 111, 117
Non-narcotic analgesics, uses of 48 laparoscopic 113t
Nonsteroidal anti-inflammatory drugs 47, localization of 108
75, 122, 169 management of 118
Nontechnical skill 141, 143, 144, 144t pediatric 105
assessment tools 143 Placental drug transfer 166
classification and categorization of 144f Plasma
genesis of 142 catecholamines 107
grading of 144 cystatin C 267
Nutrition, role of 205 free metanephrines 107
histamine 125
O Plateau pressure 215
Obesity 266 Pneumonia, ventilator associated 281
Oculocardiac reflex, reduction of 235 Pneumoperitoneum 114
Omega-3 polyunsaturated fatty acids 3, 5 Positive-end expiratory pressure 202, 210,
Ophthalmic procedures 235 214, 215
Opioids 48, 73t, 82, 134, 171 Prilocaine 72
peptide expression 85 Prism devices 191
receptor 83 Procalcitonin 271, 274
plasticity and regulation of 84 Prodynorphin 85
tolerance 174 Proenkephalin 85
transdermal 73 Propofol 134, 171
Optic neuropathy, ischemic 244 Protein
Optimal tidal volume 213 binding 165
Oral carbohydrate 155 kinase C 176
Organ dysfunction systems 53
Oxygenation 210 Q
criteria 214 Quasistatic methods 216
status 187 Quorum sensing molecule 269
P R
P-glycoprotein system, inhibition of 177 Randomized controlled trial 2, 96, 279
Pain 41 Rapydan patch 76
assessment 42 Rectus
methods of 43 abdominis muscle 33f
score 44t sheath block 32, 33f
management 50 Regional anesthesia, intravenous 97
modulation of 86 Renal failure 266
pathways 177 Reperfusion injury protection 289
postoperative 46 Respiratory distress syndrome, acute 5,
scale, postoperative 44 210, 213
Palliative care, scope of 225 Respiratory system, static pressure-volume
Pan-facial fractures 186 curve of 216f
Index 295
Resuscitation 200 cardiac 257, 260

bundle 290 noncardiac 254, 256, 256t, 260
Retrograde intubation 191 ophthalmic 231
Road-traffic accidents 184 Surgical abdominal sepsis population 57
Roizen’s criteria 110 Syndrome of inappropriate antidiuretic
Ropivacaine 170, 171 hormone secretion 205
Rostroventral medulla 177 Synera patch 76
Systemic inflammatory response
S syndrome 2, 269
Saphenous nerve 33, 37f
block 37, 37f T
Sartorius muscle 37f Temporomandibular joint 185
Scalene muscles 27f Tetracaine 72
Sciatic nerve 33, 36 Tetracycline 171
Scoliosis surgery 146 Tetrology of Fallot 259
Sedation 203, 231, 235 Thalidomide 171
Seizure 201 Therapeutic intervention scoring system
Selenium 6 53
Sequential organ failure assessment 53, Thiopentone 134
54, 59, 59t Thoracic endovascular aortic repairs 245
score 59 Thoracolumbar nerves lie 33f
Sevoflurane 171 Thrombocytopenia, heparin induced 156
Shock 266 Thromboembolism prophylaxis 156
Simplified acute physiology score Tidal volume 210, 213
53, 54, 57 Tissue necrosis factor 2
Single incision laparoscopic surgery 33 Total hip replacement 284
Society of Critical Care Medicine 59 Total knee
Society of Thoracic Surgeons 258 arthroplasty 273
Spinal replacement 284
cerebrospinal fluid 169 Total parenteral nutrition 1
cord ischemia 245 Traditional flexible fiberscope devices 191
Sports injuries 184 Transdermal
Staphylococcus aureus 281 drug delivery 68
Staphylococcus capitis 281 novel methods of 76
Staphylococcus epidermidis 281 opioids, titrations of 74
Staphylococcus haemolyticus 281 patches, design and types of 70
Staphylococcus hominis 281 Transient neurological syndrome 249
Staphylococcus warneri 281 Transtracheal jet ventilation 194
Sternocleidomastoid muscle 26 Transversus abdominis 31
Streptomycin 171 muscles 31, 32f
Stress 132 plane 30
ulcer 205 Trauma life support, advanced 186
prophylaxis 205 Traumatic brain injury 199
oxidative 5 management of 199
Stroke 246 severe 199
ST-segment elevated myocardial Traumatic subarachnoid hemorrhage 206
infarction 266 Trimethadione 171
Submandibular intubation 194 Troponins, cardiac 265
Sub-Tenon’s block 234 Truncal blocks 30
technique 234 Tumor necrosis factor 136
Supraclavicular fossa 28f
Supraglottic devices 190 U
Surgery Ulnar nerve 26f
abdominal 96 Ultrasound guided ophthalmic blocks 233
Upper extremity blocks 25 Vein, femoral 35f

Upper face fractures 185 Ventilation, mechanical 59, 210
Urinary Video-laryngoscopes 191
catecholamines 107 Vision devices 190
cystatin C 267 Visual analog scale 42
fractionated metanephrines 107 modified 42, 42f
total metanephrines 107 Volutrauma 211
Urine histamine 125 Vomiting 201
prophylaxis 158
V
Valproic acid 171
Vanillylmandelic acid 107
W
Vasoactive intestinal peptide 104 Women’s health study 265

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Yearbook of

B Radhakrishnan MD MPhil FICA

Jayashree Sood MD FFARCS PGDHHM FICA

Anjan Trikha MD FICA

Indian College of Anaesthesiologists

The Health Sciences Publisher

Jaypee Medical Inc. Jaypee Brothers Medical Publishers (P) Ltd.

Hema C Nair MD Lakshmanan Parthasarathy MD DA

Pramod Kohli MD Sachidanand Jee Bharti MD

Surender K Malhotra MD FICA Vinod Kalla DA FFARCS

B Radhakrishnan MD MPhil FICA

2. Medicolegal Issues in Anesthesia 12

3. Regional Anesthesia in Children 25

4. Pain in Children: Assessment and Management Strategies 41

5. Severity of Illness Scoring Systems and Their Clinical Relevance 53

6. Transdermal Drug Delivery 68

7. Peripheral Opioid Receptors 82

8. Dexmedetomidine: Perioperative Applications and Limitations 93

9. Pheochromocytoma: Current Concepts and Management of

10. Perioperative Anaphylaxis 121

11. Effect of Anesthesia on Perioperative Immunity 131

12. Nontechnical Skills for the Healthcare Provider:

Positive End-expiratory Pressure 214 • Concept of Driving Pressure 218

19. Palliative and Hospice Care: Need of the Hour to Improve

20. Update on Anesthesia for Ophthalmic Surgery 231

21. Perioperative Neurological Complications 242

22. Perioperative Beta Blockers: To Use or Not to Use 254

23. Biomarkers in Anesthesiology 264

Journal Scan 278

ENTERAL VERSUS PARENTERAL NUTRITION

INFLAMMATION AND IMMUNE RESPONSE

IMMUNONUTRITION AND PHARMACONUTRITION

the stress response of critical illness led to the development of specialized

ROLE OF INDIVIDUAL IMMUNONUTRIENTS

severe involvement.18 A meta-analysis in critically ill patients displayed evidence

evidence on reduction of morbidity with glutamine supplementation compared

Omega-3 Fatty Acids, Gamma-Linolenic Acid and Antioxidants

Studies directed to identify these positive effects of parenteral selenium

12. Braga M. Immunonutrition: from laboratory to clinical practice. Nutrition.

COMMON CAUSES OF LITIGATIONS

LEGAL ASPECTS OF ANESTHESIA

Table 2.1 Causative factors for perioperative complications

preventable incidents, but equipment design was indictable in many categories

Table 2.2 Allegations against anesthesiologists compiled from ASA-CCP data

• Medication events (wrong dose) 53%

Doctor-patient relationship builds a legal contract.21 An anesthesiologist

Minimum Monitoring Standards of Anesthesia

discuss possible complications and possible change in anesthesia plan while

INTRAOPERATIVE LEGAL REQUISITES

Response to an Adverse Event

POSTOPERATIVE LEGAL REQUISITES

Care of a Patient after the Bad Outcome

STRATEGIES TO REDUCE ADVERSE PATIENT OUTCOMES

ELEMENTS OF MEDICAL NEGLIGENCE

TIME LIMITATION AND COURT JURISDICTION24

OUTCOME OF A COURT TRIAL

UPPER EXTREMITY BLOCKS

complications but rather as expected. Caution should be taken when considering

Transversus Abdominis Plane Block

• Medication events (wrong dose) 53%