Yearbook Anaesthesiology

Yearbook of
Anesthesiology-9
Editorial Board
1. VP Kumra MD DAc FICA
Emeritus Consultant and Advisor
Department of Anesthesiology, Pain and Perioperative Medicine
Sir Ganga Ram Hospital, New Delhi, India
Past President and Advisor
Indian College of Anaesthesiologists
Former Vice President
Indian Society of Anaesthesiologists (National)
ved_kumra@yahoo.com
2. B Radhakrishnan MD MPhil FICA

Senior Professor and Consultant
Sree Gokulam Medical College and GG Hospital
Trivandrum, Kerala, India
President
Former President
Indian Society of Anaesthesiologists (National)
brktvm@yahoo.com
3. Jayashree Sood MD FFARCS PGDHHM FICA

Professor and Chairperson
Department of Anesthesiology, Pain and Perioperative Medicine
Honorary Joint Secretary, Board of Management
CEO, Indian College of Anaesthesiologists
jayashreesood@hotmail.com
4. Baljit Singh MD FICA

Former Director Professor
GB Pant Institute of Postgraduate Medical Education and Research
New Delhi
Professor Anesthesia
Faculty of Medicine and Health Sciences
SGT University, Gurugram, Haryana, India
drbaljitsingh@gmail.com
Yearbook of
Anesthesiology-9
Editors
Raminder Sehgal MD DA FICA
Maulana Azad Medical College, New Delhi
Former Senior Consultant
ramindersehgal@hotmail.com
Anjan Trikha MD FICA

Professor
All India Institute of Medical Sciences
New Delhi, India
anjantrikha@gmail.com
Foreword
Baljit Singh
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Yearbook of Anesthesiology-9
First Edition: 2020
ISBN: 978-93-89188-90-5
Contributors
Anita Mathew MD Babita Ghai MD
Assistant Professor Professor
Department of Anesthesiology Department of Anesthesiology and
Believers Church Medical College Hospital Intensive Care
Thiruvalla, Kerala, India Postgraduate Institute of Medical
dranitageomcy@gmail.com Education and Research
Chandigarh, India
Anju Romina Bhalotra MD ghaibabita1@gmail.com
Director Professor
Department of Anesthesiology Bhuwan Chand Panday MD
Maulana Azad Medical College Consultant
New Delhi, India Department of Anesthesiology, Pain and
drakgk@yahoo.co.in Perioperative Medicine
Sir Ganga Ram Hospital
Anoop Raj Gogia MD New Delhi, India
Consultant and Professor bhuwancp@gmail.com
Department of Anesthesia and Intensive
Care Brig RM Sharma MD
Vardhman Mahavir Medical College and Consultant and Head
Safdarjang Hospital Anesthesiology and Critical Care
New Delhi, India Army Hospital (R&R)
gogiaanoop@gmail.com New Delhi, India
sharmarammurti@gmail.com
Arun Maheshwari MD
CK Dua DA MD FICA
Chairman (Cardiac Anesthesia)
Former Director Professor and Head
Dharma Vira Heart Centre
Anesthesiology
Sir Ganga Ram Hospital
Maulana Azad Medical College and Lok
New Delhi, India
Nayak Jai Prakash Hospital, New Delhi
drarunmaheshwari@gmail.com
Former Professor and Head
(Anesthesiology)
Asha Tyagi MD DNB MNAMS Santosh Medical College and Hospital
Director Professor Ghaziabad, Uttar Pradesh, India
Department of Anesthesiology and dr.ckdua@gmail.com
Critical Care
University College of Medical Sciences and Deep Arora MD
Guru Teg Bahadur Hospital Director (Orthopedic Anesthesia)
New Delhi, India Medanta—The Medicity
drashatyagi@gmail.com Gurugram, Haryana, India
drdeeparora@yahoo.com
Ashu Sara Mathai MD
Vice Principal and Professor Deepak Pahwa MD
Department of Anesthesiology Consultant (Orthopedic Anesthesia)
Believers Church Medical College Hospital Medanta—The Medicity
Thiruvalla, Kerala, India Gurugram, Haryana, India
ashumathai@gmail.com pahwadoc@hotmail.com
vi Yearbook of Anesthesiology-9
Devalina Goswami MD Kumar G Belani MS FACA FAAP

Associate Professor Professor
Department of Anesthesiology, Pain Department of Anesthesiology
Medicine and Critical Care University of Minnesota
All India Institute of Medical Sciences Minneapolis, Minnesota, USA
(AIIMS) kumarbelani@gmail.com
New Delhi, India
drdevalina@gmail.com Lakesh Kumar Anand MD FIMSA FCCP MAMS
Professor of Anesthesia
Elvin Daniel MD FIACTA Department of Anesthesia and Intensive
Associate Consultant (Cardiac Anesthesia) Care
Dharma Vira Heart Centre Government Medical College and Hospital
Sir Ganga Ram Hospital Chandigarh, India
New Delhi, India lkanand@gmail.com
daniel.elvin@gmail.com
Lokesh Kashyap MD
Gita Nath MD DA DNB FFARCS Professor
Consultant (Anesthesia and Intensive Care) Department of Anesthesiology, Pain
Medicine and Critical Care
Axon Anesthesia Associates
All India Institute of Medical Sciences
Hyderabad, Telangana, India
(AIIMS)
drgitanath@hotmail.com
New Delhi, India
lokeshkashyap@yahoo.com
Himanshu Suri DA
Senior Consultant M Subrahmanyam MD DNB DA (UK) FRCA
Department of Anesthesia Consultant (Anesthesia and Intensive Care)
Medanta Institute of Musculoskeletal Axon Anesthesia Associates
Disorders and Orthopedics Hyderabad, Telangana, India
Medanta—The Medicity msubrah@gmail.com
Gurugram, Haryana, India
himanshusuri@yahoo.com Magesh Parthiban MD
Senior Resident
JP Attri MD Department of Anesthesiology, Pain
Professor Medicine and Critical Care
Department of Anesthesia All India Institute of Medical Sciences
Government Medical College (AIIMS)
Amritsar, Punjab, India New Delhi, India
jpattri12@yahoo.co.in magesh.268@gmail.com
Kapil Dev Soni MD Maj Gen Rashmi Datta VSM MD MG (Med)

Associate Professor Senior Consultant
Critical and Intensive Care Anesthesiology and Critical Care
Jai Prakash Narayan Apex Trauma Centre Base Hospital, Delhi Cantt and
All India Institute of Medical Sciences Army Hospital (R&R), New Delhi, India
New Delhi drrashmidatta@gmail.com
kdsoni111@gmail.com
Manpreet Singh MD FCCP FIMSA FACEE FCCS
Kirti N Saxena MD MAMS
Director Professor and Head Associate Professor
Department of Anesthesiology and Department of Anesthesia and Intensive Care
Intensive Care Government Medical College and Hospital
Maulana Azad Medical College Chandigarh, India
New Delhi, India manpreetdawar@ hotmail.com,
kirtinath@gmail.com manpreetdawar@gmail.com
Contributors vii
Neetu Jain MD DNB Purnima Dhar MD

Senior Consultant Senior Consultant (Anesthesia and Critical
Department of Anesthesiology, Pain and Care)
Perioperative Medicine Indraprastha Apollo Hospital
Sir Ganga Ram Hospital New Delhi, India
New Delhi, India purnima29@gmail.com
drneetujain@yahoo.com
Rahil Singh DA DNB
Assistant Professor
Neha Agrawal DA DNB MBA (HCA) Department of Anesthesiology
Regional Quality Head (North)—Narayana Maulana Azad Medical College
Health New Delhi, India
Senior Consultant Anesthesiology drrahilsingh@gmail.com
Dharamshila Narayana
Superspecialty Hospital Ranjana Khetarpal MD
New Delhi, India Professor
neha.agrawal.dr@narayanahealth.org Department of Anesthesia
Government Medical College
Amritsar, Punjab, India
Nitika Goel MD
rkhetarpal9@hotmail.com
Assistant Professor
Department of Anesthesiology and Rashmi Salhotra MD
Intensive Care Associate Professor
Postgraduate Institute of Medical Department of Anesthesiology and
Education and Research Critical Care
Chandigarh, India University College of Medical Sciences and
nitikagoel7@gmail.com Guru Teg Bahadur Hospital
New Delhi, India
Pallavi Ahluwalia MD PDGHHM CCEPC FIMSA rashmichabra@gmail.com
Professor of Anesthesiology
Reeta Singh MD DNBE MBA (HCS)
Department of Anesthesia, Pain and
Dip Interventional Pain
Palliative Medicine Consultant Anesthesiologist
Teerthanker Mahaveer Medical College Awali Hospital
and Research Center Kingdom of Bahrain
Moradabad, Uttar Pradesh, India reeta_singh@bapco.net
drpallaviahluwalia@yahoo.com
Richa Aggarwal MD
Payal Jain MD Associate Professor
Assistant Professor Critical and Intensive Care
Department of Anesthesia, Pain and Jai Prakash Narayan Apex Trauma Centre
Perioperative Medicine All India Institute of Medical Sciences
Teerthanker Mahaveer Medical College New Delhi, India
pathakricha@yahoo.co.in
and Research Center
Moradabad, Uttar Pradesh, India
payaljain27@yahoo.co.in Roberto C Blanco MD
Assistant Professor
Department of Anesthesiology
Preet Mohinder Singh MD Regional Anesthesia Division
Assistant Professor of Anesthesiology Co-director Regional Anesthesia Fellowship
Washington University School of Medicine University of Minnesota
Saint Louis, Missouri, USA Minneapolis, Minnesota, USA
singh.p@wustl.edu rblancod@umn.edu
viii Yearbook of Anesthesiology-9
Sanjay Sharma MD FANZCA GCCS MHSM Susheela Taxak DA MD DNBE

Associate Professor and Deputy Director Senior Professor
Department of Anesthesia Department of Anesthesiology
Ballarat Health Services Pt Bhagwat Dayal Sharma Postgraduate
Ballarat, Victoria, Australia Institute of Medical Sciences
sanjay@sharmas.com.au
Rohtak, Haryana, India
susheelataxak@gmail.com
Saurabh Kumar Das MD PDCC IFCCM EDIC
Senior Consultant (Critical Care)
Artemis Hospital Swarup Sri Varaday MD FRCA FCARSI
Gurugram, Haryana, India Associate Professor of Anesthesiology
dassk1729@gmail.com Washington University School of
Medicine
Shreya Goswami MD Saint Louis, Missouri, USA
Clinical Research Associate varadays@wustl.edu
Department of Anesthesiology
University of Washington Vinh Nguyen DO
St Louis, Missouri, USA Assistant Professor
shreya.goswami@wustl.edu Department of Anesthesiology
University of Minnesota
Sumit Ray MD FICCM Minneapolis, Minnesota, USA
Chairperson of Critical Care
vhnguyen04@gmail.com, nguyenv@umn.
Artemis Hospital
edu
drsray67@yahoo.co.in
Surinder Mohan Sharma MD DMICAc FICA

Chairman
Department of Anesthesia
Medanta Institute of Musculoskeletal
Disorders and Orthopedics
Medanta—The Medicity
drsms1@gmail.com
Foreword
Anesthesiology is a rapidly growing specialty and anesthesiologists need
to keep pace with the ever-increasing demands of patients with associated
medical disorders presenting for surgery. From behind the curtain role to
a commanding position in the management of patients, anesthesiologists
play a significant role not only in the operating room but beyond also.
Indian College of Anaesthesiologists has been playing an important role by
bringing out the new developments in the field of anesthesiology through
Yearbook of Anesthesiology every year for the last eight years. Yearbook of
Anesthesiology-9, now ready for release has topics that have been very well
chosen with regard to coverage in the previous editions and the impact of
the latest research on the practice of anesthesiology.
The editors, Drs Raminder Sehgal and Anjan Trikha have been doing
a great job in selecting the contributors who have exceled in their chosen
fields. The chapters have been written and edited to make the text easy-to-
understand and comprehend. Yearbook of Anesthesiology-9 promises to be
an invaluable asset to learning process for the anesthesiologists of every
stature, particularly the younger generation. The book is unique in the sense
that it does not follow the conventional “system by system” chapters but
brings out the newer insights into the science of patient care that would
widen the knowledge base of all those reading it.
I sincerely believe this book would go far and wide and adorn the tables
of the scientifically oriented.
Congratulations to the editors for a well-crafted work of science and my
compliments to the contributing authors for the excellent write up.
Baljit Singh MD FICA

GB Pant Institute of Postgraduate
Medical Education and Research
New Delhi
Professor Anesthesia
Faculty of Medicine and Health Sciences
SGT University, Gurugram, Haryana, India
drbaljitsingh@gmail.com
Preface
The present Yearbook of Anesthesiology is the 9th edition in the series of
yearly handbook published under the auspices of the Indian College of
Anaesthesiologists. All the previous editions have been appreciated by all–
practicing anesthesiologists, teaching faculty members in anesthesia and the
postgraduate students. It is our endeavor to choose topics from all fields of
anesthesiology; especially those that have importance in the present times
of changing patient profile or anesthesia practice in our country.
In this regard, the chapter on management of an obese parturient and
pregnancy induced hypertension are very informative. Indian population is a
mix of malnourished and overweight patient, and it is very relevant in todays
practice to be aware of issues that need to be addressed in obese parturients.
The use of smart phones has changed the way, medicine is practiced in
today’s world especially as far as drug interactions, side effects and doses
are concerned. The chapter of smart phones discusses its advantages and
the nuisance values in anesthesia practice. A very informative detailed yet
concise article is on sugammadex, the new reversal agent that has been
introduced in our country. We are sure that both students and practicing
personnel would find it very informative and useful. In the same context,
the recently available high flow nasal cannula systems have been discussed
in another chapter.
Of special interest to all anesthesiologists practicing regional anesthesia
would be the chapter on phrenic nerve sparing brachial plexus blocks.
Other issues of importance include errors in medicine, health hazards in the
anesthesiologists, infection prevention and intraoperative thermoregulation.
Chapters on weaning from mechanical ventilation and nutrition should
interest those managing critically ill patients. Anesthetic issues in the
management of patients from extreme of age, whether geriatric or pediatric,
have been dealt with in detail.
The chapter on the present status of platelet rich plasma in chronic pain
conditions and degenerative diseases is likely to be of immense benefit to
all pain specialists. Such injections are being used very frequently in our
country for a lot of conditions with varying results. Two chapters that are
likely to be of extreme importance to postgraduates are those on double
lumen endotracheal tubes and gas embolism. Both manuscripts have all
possible information on the subjects in a very condensed form with details
of standard references for future readings. Perioperative management of
high altitude pulmonary edema, hyperglycemia, daycare arthroplasty and
xii Yearbook of Anesthesiology-9
neurovascular procedures have been covered along with complications

such as postoperative myocardial injury and postoperative delirium.
Like in all previous editions, this yearbook also has a section on Journal
Scan where landmark articles in the previous year are opined upon by
leading experts in their fields.
Both of us would take this opportunity to thank all the authors form
India and abroad who were able to accept our invitations to write the
manuscripts and submit them within the time frame required.
A special word of appreciation is in order for the staff of M/s Jaypee
Brothers Medical Publishers (P) Ltd, New Delhi, India, for their support
for patiently working with us in bringing out this edition of the Yearbook of
Anesthesiology.
Raminder Sehgal
Anjan Trikha
Contents
1. Errors in Medicine: A Perioperative Perspective....................1
Sanjay Sharma
• Incidence 2
• Classification of Errors Based on Causation—
Active or Latent 2
• Is the Term “Error” the Most Appropriate and Suitable? 5
• Role of Human Factors in Genesis of Error 6
• “Highly Complex, Tightly Coupled” 6
• Changing Approach to Error 7
• Causation of Errors also Mired in Myths 8
• Medication Errors in the Hospital 9
• Classification of Medical Errors Based on Impact 10
• Medication Errors Specific to the Practice of Anesthesia 10
• Error Reduction and Prevention—Harm Minimization 14
• Management of Erroneous Administration of Medication 16
2. Perioperative Care of the Frail Elderly:

Current Knowledge and Future Directions............................22
Asha Tyagi, Rashmi Salhotra
• Who is an Old Patient? 22
• What is Frailty? 22
• How to Recognize Frailty? 23
• Pathophysiology of Frailty 25
• Risk Factors for Frailty 25
• Implications of Frailty 26
• “Frail Body” or “Frail Organ System” 26
• Should Preoperative Assessment Focus on Frailty Only? 28
• Anesthesia in the Frail Elderly 28
• Interventions to Improve or Modify Outcome in Frailty 30
3. Pregnancy-induced Hypertension: An Update .....................34

CK Dua
• Classification of Pregnancy-induced Hypertension 34
• Definition of Pregnancy-induced Hypertension Disorders 35
• Pathogenesis of Pre-eclampsia 37
• Risk Prediction and Prophylaxis of Pre-eclampsia 38
xiv Yearbook of Anesthesiology-9
• Systemic Manifestations of Severe Pre-eclampsia 40

• Obstetric Management 42
• Anesthetic Management of Pre-eclampsia 46
• Nonoperative Delivery: Labor Analgesia 46
• Operative Delivery: Anesthetic Management 47
4. Sugammadex and Beyond......................................................55

Vinh Nguyen, Kumar Belani
• Sugammadex versus Anticholinesterase Inhibitors 55
• Special Considerations 57
• Adverse Effects 59
• Relative Contraindications and Cautions 60
• Future Reversal Agents 61
5. Issues and Management of Obese Parturient.......................68

Swarup Sri Varaday, Preet Mohinder Singh
• Defining Obesity in Pregnancy—the Dilemma! 69
• Epidemiology—the Change in Lifestyle 69
• Pathophysiology of Obesity in Pregnancy 70
• Obese Parturient and Anesthesiologist 70
• Obstructive Sleep Apnea 71
• Labor Analgesia 76
• Anesthesia for Cesarean Section 77
• Postoperative Management 79
6. Postoperative Delirium: A Bane of Daycare Surgery............85

Deep Arora, Deepak Pahwa
• Importance of Postoperative Delirium 85
• Definition and Incidence 86
• Pathophysiology of Postoperative Delirium 86
• Risk Factors for Development of Postoperative Delirium 87
• Clinical Presentation and Diagnosis 88
• Delirium Screening 89
• Differential Diagnoses 91
• Prediction of Postoperative Delirium 91
• Biomarkers 93
• Prevention and Treatment of Postoperative Delirium 93
• Cognitive Outcome of Postoperative Delirium 95
7. Gas Embolism: An Update......................................................99

Anju Romina Bhalotra, Rahil Singh
• Epidemiology 99
• Etiology 100
Contents xv
• Pathophysiology 101
• Clinical Presentation 103
• Detection 104
• Differential Diagnosis 106
• Prevention 106
• Management 107
• Special Situations 109
8. Nutrition in the Intensive Care Unit......................................115
Richa Aggarwal, Kapil Dev Soni
• Assessment of Nutritional Status 116
• Patients at Risk of Malnutrition 116
• Initiating Nutrition 116
• Early Enteral Nutrition versus Delayed Enteral Nutrition versus
Parenteral Nutrition 117
• Energy and Protein Requirement of Critically Ill Patients 118
• How to Provide Enteral Nutrition? 119
• Parenteral Nutrition 121
• Adjunctive Therapy 122
• Nutrition in Various Disease Conditions 124
• Monitoring Nutrition 125
• Appendix 1: Nutric Score 127
• Appendix 2: Comparison of Various Parenteral
Formulations Available 128
9. Smartphones in Anesthesia: Game Changers or

Mere Distractions? ................................................................133
Ranjana Khetarpal, JP Attri
• Mobile Information Technology Applications in
Hospital Scenario 134
• Disease Prevention and Health Promotion 136
• Smartphone as a Cost-effective Ventilator 136
• Concerns Arising Out of Mobile Use in Hospitals 137
• Smartphones and the Medical Equipment 139
• Guidelines Regarding Safe Use of Smartphones 140
• Ethical and Legal Issues with Smartphone Use 140
• Summary and Conclusions 140
10. Health Hazards for an Anesthesiologist:

A Myth or Reality?..................................................................145
Susheela Taxak, Reeta Singh
• Physical Hazards 147
• Mental Hazards 150
• Other Hazards 152
xvi Yearbook of Anesthesiology-9
11. Effect of Anesthesia on the Developing Brain:

A Review of Recent Evidence ..............................................157
M Subrahmanyam, Gita Nath
• Neurotransmitters in the Brain 157
• Evidence from Animal Studies 159
• Clinical Studies 161
• Maternal Anesthesia and its Effects on the Fetus 165
12. Weaning from Mechanical Ventilation .................................173

Saurabh Kumar Das, Sumit Ray
• Stages of Mechanical Ventilation 174
• Conventional Methods of Weaning 177
• Comparison of Different Conventional Modes of Weaning 178
• Ventilator Modes for Weaning 178
• Weaning Protocol 180
• Weaning Failure 180
• Management of Prolonged Weaning Failure 183
• Other Related Issues 184
13. Intraoperative Thermoregulation .........................................190

Ashu Sara Mathai, Anita Mathew
• Mechanisms Underlying Thermoregulation 191
• Monitoring of Body Temperature 192
• Causes of Thermal Dysregulation in the Perioperative Period 192
• Extent of the Problem 194
• Consequences of Inadvertent Perioperative Hypothermia 194
• Management of Intraoperative Hypothermia 196
• Methods of Warming 198
14. Platelet-rich Plasma for Management of Chronic

Pain and Degenerative Conditions: A Critical
Review of Evidence ...............................................................203
Babita Ghai, Nitika Goel
• What is Platelet-rich Plasma? 203
• Types of Platelet-rich Plasma 204
• Proposed Mechanism of Platelet-rich Plasma? 204
• Does Proposed Mechanism of Platelet-rich
Plasma Work in vivo? 205
• Clinical Evidence of Platelet-rich Plasma in
Osteoarthritis Knee 205
• Clinical Evidence of Platelet-rich Plasma in Chronic Low
Back Pain 206
Contents xvii
• Current Use of Platelet-rich Plasma in Musculoskeletal

Tissues 209
• Adverse Events with Platelet-rich Plasma 210
15. Postoperative Myocardial Injury: Causes and

Management ..........................................................................215
Arun Maheshwari, Elvin Daniel
• Definition of Myocardial Infarction: Does Postoperative
Myocardial Injury Fit In? 215
• Does Postoperative Myocardial Injury always mean
Myocardial Infarction? 216
• Diagnosis 217
• Risk Prediction 219
• Prevention and Management 220
16. Management of Hyperglycemia in the

Perioperative Period .............................................................226
Pallavi Ahluwalia, Payal Jain
• Diagnostic Criteria for Diabetes Mellitus 226
• Implications of Surgery on Blood Sugar Levels 227
• Types of Anesthesia and its Effect on Blood Glucose 227
• Anesthetic Drugs and their Effects on Blood Glucose 228
• Assessment during Perioperative Period and
Management Goals 229
• Glycemic Goals in Perioperative Period 229
• Nutrition and Nutritional Intake 230
• Approaches to Improve Perioperative Glycemic Control 230
• New and Improved Insulin Delivery Devices 234
• Glycemic Management in Intraoperative Period 234
• Hypoglycemia 236
• Glycemic Management in Postoperative Period 236
• Special Scenarios 238
• Conflict of Interest 240
17. Challenges and Issues in Daycare Arthroplasty ................244

Surinder Mohan Sharma, Himanshu Suri
• Definition of Daycare or Outpatient Arthroplasty 244
• Why Daycare Total Joint Arthroplasty 245
• Components of an Outpatient Total Joint
Arthroplasty Program 245
• Patient Selection 246
xviii Yearbook of Anesthesiology-9
• Patient Education and Social Optimization 247

• Intraoperative Considerations 248
• Anesthesia 248
• Surgical Technique 249
• Analgesia 250
• Deep Venous Thrombosis Prophylaxis 250
• Postdischarge Care 250
• The Indian Perspective 251
18. Anesthesia for Neurovascular Procedures ........................256

Neetu Jain, Bhuwan Chand Panday
• Intracranial Aneurysms 256
• Arteriovenous Malformation 268
• Endovascular Therapy for Other Procedures 273
19. High-flow Nasal Oxygenation: A Fad? ................................277

Manpreet Singh, Lakesh Kumar Anand
• Equipment for High-flow Nasal Oxygenation 278
• Physiological Basis for Use of High-flow Nasal Oxygen 278
• Current Clinical Applications 279
• Indications of High-flow Nasal Oxygen in Critical Care 281
• Indications and Procedures in Anesthesia 284
20. Double-lumen Endotracheal Tubes: From History to

Present and the Future .........................................................293
Lokesh Kashyap, Magesh Parthiban
• History of Double-lumen Tubes 295
• Modern Double-lumen Tubes 297
• Selection of Appropriate Size 300
• Method of Insertion and Confirmation of Proper Placement 301
• Confirmation of Proper Placement 301
• Recent Advances in Double-lumen Tube 303
21. High-altitude Pulmonary Edema...........................................308
Rashmi Datta, RM Sharma
• History 309
• Physiology at High Altitude 312
• Epidemiology and Risk Factors 315
• Clinical Presentation 317
• Investigations 318
• Differential Diagnosis 319
• Treatment 320
• Prevention 323
Contents xix
22. Infection Prevention in the Operating Room.......................328

Neha Agrawal
• Infrastructure Measures 329
• Behavioral Measures 333
• Clinical Measures 341
• Disinfection and Sterilization Measures 341
• Surveillance Protocol 346
23. Regional Blocks for Shoulder Surgery:

Sparing the Phrenic Nerve....................................................353
Roberto C Blanco, Kumar G Belani
• Anatomical Considerations 354
• Practical Implications 356
• Specific Blocks 358
24. Current Status of Methylene Blue in Anesthesia and

Intensive Care.........................................................................363
Devalina Goswami
• Historical Background 363
• Physiochemical Properties 363
• Mechanism of Action 364
• Effect of Methylene Blue on Anesthetics 365
• Treatment of Methemoglobinemia 365
• Vasodilatory Shock 366
• Cardiac Surgery and Vasoplegia 366
• Sepsis 368
• Anaphylactic Shock 368
• Orthotopic Liver Transplantation 369
• Cardiovascular Drug Poisoning 369
• Ifosfamide Toxicity 369
• Hydrogen Sulfite Toxicity 370
• As An Indicator Dye 371
• Adverse Effects 371
• Serotonin Toxicity 372
• Contraindications 372
25. Journal Scan ..........................................................................377

Kirti N Saxena, Shreya Goswami, Purnima Dhar, Anup Raj Gogia
• Journal Scan 1—Kirti N Saxena 377
• Journal Scan 2—Shreya Goswami 380
• Journal Scan 3—Purnima Dhar 384
• Journal Scan 4—Anup Gogia 388
Index...............................................................................................395
Errors in Medicine: A Perioperative Perspective 1
CHAPTER
1 Errors in Medicine: A
Perioperative Perspective
Sanjay Sharma
INTRODUCTION
There is increasing emphasis on minimizing medical errors, which have been
described as “an act of omission or commission in planning or execution
that contributes or could contribute to an unintended result”.1 Realistically,
this would include both the implementation of an inappropriate plan, or a
good plan not executed as intended. These errors are usually unintentional
and not malicious or deliberate.
The errors of omission or commission, in both planning and execution
of various processes, are included irrespective of whether the adverse
outcome actually occurred or was likely. It thus provides a useful template
for research into faulty processes that contribute to majority of errors that
could fly under the radar, as they do not actually cause harm. Equally, it
takes focus away from trivial “slip ups” that do not have the potential to
actually result in an adverse outcome.
The healthcare industry is inspired by, and follows the model of the
airline industry by investigating every near miss and error. This initiative,
to analyze each event irrespective of whether it actually eventuates in a
bad outcome, would improve reliability and safety. The healthcare industry
aspires to achieving this level of investigation in the absence of a culture of
blame.
As opposed to unplanned errors, the term violation applies to planned
and deliberate deviation from accepted protocols and standard operating
procedure.2 Violations may sometimes involve extenuating circumstances
with pressures of time or staffing, and also include deliberate flouting
of rules in some instances. Omission of an appropriate preoperative
assessment, waiving the “time out” process, and omitting to check the
anesthetic machine prior to commencement of procedure all constitute
violations.
Moyen et al.3 clearly defined these errors, but then also further defined
medication errors, especially those that were preventable. Other definitions,
with errors subdivided into slips and lapses have also been alluded to, and
these will be discussed further in the chapter.
2 Yearbook of Anesthesiology-9
INCIDENCE
There is increasing recognition and attention to medical errors irrespective
of the actual severity of outcome. “The real problem is not how to stop
bad doctors from harming, even killing, their patients. It is how to prevent
good doctors from doing so”.4 The Institute of Medicine report,5 aptly titled
“To Err is Human”, estimated that between 44,000 and 98,000 hospitalized
patients die annually in the USA as a result of medical errors. Australian
Healthcare Quality study,6 found that adverse events (unintended injury
or complication caused by healthcare) occurred in 16.6% of hospital
admissions, with 51% of these events judged to be “highly preventable”.
UK report7 found that medical errors caused harm (death and injury) to
in excess of 850,000 patients admitted to National Health Service Hospitals
annually. Other reports, published worldwide, show widespread acceptance
of the impact of medical errors on patients admitted to hospitals.8-11
CLASSIFICATION OF ERRORS BASED ON

CAUSATION—ACTIVE OR LATENT
Errors can broadly be classified into active errors as those occurring around
an incident, and latent or systemic errors that may not be immediately
evident or visible.12
Active errors are usually attributable to personnel directly caring for
patients, such as nursing and medical staff. An example of an active error
is inadvertent administration of a wrong medication, operation performed
on wrong site, or even wrong patient. These errors may sometimes be one-
off, due to carelessness or negligence, but sometimes a reflection of latent
errors—an accident waiting to happen.
Latent errors are often systemic, resulting from poor planning or
execution. In the scenario of a wrong medication being administered,
the latent error potentially is that of two distinctly different medications
packaged in similar looking ampoules, and placed close together on the
trolley—an absolute recipe for disaster. This error would not be identifiable
until an active error was made and attributed to this problem on one or
more occasions.
Active Errors
Active errors, directly attributable to personnel, have further been classified
into simple omissions such as slips and lapses, and a third category of
fixation errors.12,13 Slips and lapses are exactly occurring frequently when one
is preoccupied or distracted and hence cannot focus appropriately on the
job they are meant to do.12 Slips and lapses can involve errors attributable
to subconscious and conscious cognition.13
Slips
Explanation of the etymology of slip suggests an unintended action or
word, such as slip of the tongue or slip up. Rotating the wrong knob on an
anesthetic machine, thus delivering nitrous oxide instead of air, is a classic
example of anesthetic slip. Though slips seem fairly innocuous, they can
sometimes result in adverse outcomes. Clarity on slips in anesthesia was
provided by Norman14 who categorized slips into sequence errors, description
errors, and mode errors.
• Sequence errors: Elements of a task are all performed, but in an incorrect
order or sequence. A typical example would be injection of muscle
relaxant before actually giving induction agent.
• Description errors: Correct action performed, but on the wrong agent
or object. This is exemplified by an appropriate action such as turning
off the knob, but wrongly the knob of nitrous oxide rather than oxygen.
• Mode errors: Performance of correct action but the setting of equipment
is in the incorrect or wrong mode. Once the circuit switch is set to
ventilator mode, attempts to squeeze a breathing bag to ventilate the
patient highlights a mode error.
Lapse
When an intended action is missed, often due to distraction or time
pressure, it qualifies as a lapse. Leaving one’s car unlocked and rushing
into a shopping center is a typical example of a lapse. In clinical work, a
lapse occurs when a medication is not given though it was intended to.
Fixation Error
This is a third variety of active error, seen more commonly in a crisis or
stressful situation. Allnutt14 describes extreme concentration on one action
at the cost of other more useful actions as “coning of attention”. He describes
this tendency to focus on a particular task or source of information without
“taking a step back” to review others options. Some emergency situations
call for a change in plan or diagnosis but the persistent failure to recognize
this and stick to the original unsuccessful action is a classic example of
fixation error.15 An example would be the ongoing attempt to “fight” with
a piece of jammed essential lifesaving equipment rather than picking an
alternative which may be easily available.
Few common types of fixation errors are:
• “This and only this”: In this scenario, the caregiver is fixated on a
diagnosis and will not consider alternative plans despite investigations
suggesting otherwise.
• “Everything but this”: Another variety where the caregiver does not
acknowledge a major problem and hence this is left unattended, while
minor issues are attended to.
• “Everything’s okay”: Similar to the above, where evidence is ignored to
the detriment of the condition.
A classic example of fixation error was evidenced in a 1972 plane crash,
where the crew gave all their attention to a defective indicator light. So
fixated were they on this light that they ignored a major looming disaster
with autopilot disengaging until the plane actually crashed.
Simulation exercises for anesthetic emergencies often display fixation
errors, irrespective of the seniority and experience of the anesthesiologist.16,17
A positive approach to this error and reflection on methods to avoid this in
real life serves a purpose of simulation exercise.
Latent Errors
Why do errors occur repeatedly? Bogner’s theory of error scripts—“all the
men and women are merely players”.18 He suggests that the script may
incorporate faults, which induce or provoke errors, and this sets the stage
for adverse outcomes. The individuals held responsible are actually merely
“actors” and should not be the focus of punitive action, since they are mostly
“following a script”.
Anesthesia is unique in that one practitioner singlehandedly decides
the medication to be administered, prepares, and administers it and
then monitors the patient to ensure that no complication ensues. This is
complex at the best of times, and provides a template for mishaps and errors
especially in times of stress or crisis.
Recently, there have been news items relating to adverse outcome
when tranexamic acid was injected intrathecally as the ampoule was
similar to bupivacaine, and easily mistaken. Both had orange-colored
lettering, and were placed side-by-side on a trolley. Another such potential
disaster related to similarity between ondansetron and vasopressin causing
accidental injection of the wrong agent. Errors relating to accidental
intrathecal injection of chemotherapeutic agents meant for intravenous
administration have been reported on many occasions both in UK and
Australia.19 Despite extensive publicity, litigation and large payouts, beside
a manslaughter conviction, these errors have recurred. It emphasizes the
lesson from Bogner’s theory that the script is error-prone. Two medications,
one intended for intravenous administration and the other for intrathecal
injection, are packaged similarly, in similar volumes, and presented to
the doctor (“actor”) for administration. The error recurs despite changing
doctors, because the script is unchanged.
Whilst medical errors resulting in adverse outcomes are often the subject
of scrutiny, root cause analysis, and litigation, it is moot to remember that
Fig. 1: James Reason’s “Swiss cheese” model of causation of errors.21 Typically, defense
is formed by multiple layers, and when the holes align in the form of medical errors,
a poor outcome ensues.
adverse outcomes actually follow only in a small proportion. The larger

proportion of errors or “near misses” may not be associated with adverse
outcomes either due to good fortune, or to being noted and dealt with in a
timely manner.5,20
The Swiss cheese model of error causation proposed by James Reason
has been extrapolated to healthcare.21 The principle of Swiss cheese theory
suggests that several layers of defense are in place in most hospitals to
protect against adverse outcomes relating to medical errors. These layers
are represented by several slices of Swiss cheese, each with holes in them.
These holes are representative of flaws in the system, predisposing to error.
When a situation arises in which the holes in different layers align, or flaws
“match up”, injury and adverse outcomes are likely as illustrated in Figure 1.21
IS THE TERM “ERROR” THE MOST

APPROPRIATE AND SUITABLE?
Near miss,1 incident, and accident23,24 are other terms that have been used in
some safety critical industries. However, the term error carries a connotation
of stigma, and is often associated with negative psychological impact on the
clinician. An antagonistic term that strongly promotes the blame game, an
error can also be used as the basis for a malpractice claim.25-27 This fear
adds to feelings of anger, inadequacy, guilt, anxiety, and depression.5,20,28 A
negative approach such as this carries the potential to decrease efficiency
of the “accused” clinician, sometimes even resulting in them giving up an
otherwise good career in medicine.20 It has been suggested that the term
error be restricted to processes for redesigning of systems and improvement
of patient safety. Identifying error and providing feedback and education
have been acknowledged as good resources to improve patient safety.5,20,29,30
As per the Swiss cheese theory, multiple complex factors contribute

to causation of errors.12,22 The human factor needs to be factored into the
understanding of error occurrence, which is often lacking given intolerance
by public and the law. Prevention of errors is more likely to be resolved by
education, as well as addressing underlying systemic causes, and not by
punitive action against clinicians. Ultimately errors can be reduced or
mitigated once health systems are safer, not by apportioning blame and
punishing individuals.5,20,22,31 Errors need to be recognized and acknowledged
to then create educational opportunities and improvements in safety of
healthcare.26
ROLE OF HUMAN FACTORS IN GENESIS OF ERROR

Human factors involve the complex interaction between humans and
environment or technology.22 In medical field, the subset most frequently
studied was anesthesia and intensive care, which have similarities to
previously studied fields such as engineering, design, management, and
ergonomics.32 Not only is the field of anesthesia most studied for human
factors in accident causation, but is also identified as significantly invested
in strategies for patient safety.33,34 With inspiration from aviation industry
especially in relation to checklists, drills and simulation, this specialty
has made rapid advances in use of technology for patient monitoring and
implementation of safety guidelines. Analysis of human factor in causation
of errors suggests 64–83% of anesthetic accidents can be linked to human
error.13
The causes of human error in aviation mishaps were identified but not
limited to long working hours causing fatigue with flawed cognition and
decision making processes. Team issues relating to teamwork, leadership,
and interpersonal communication all potentially contribute to human
error.35 Following this analysis, attempts were made to decrease errors
through crew resource management (CRM), which has become increasingly
sophisticated and had increasing uptake and approval.36 Initial resistance
was overcome with improved training and evidence of human factors in
causation of accidents.
The specialty of anesthesia has followed the strategies implemented
in the aviation industry toward safer practice. Besides technical skills and
knowledge, anesthesiologists’ nontechnical skills (ANTS) including task
management, teamwork, situation awareness, and decision-making are
taught and assessed in the anesthesia training program.37
“HIGHLY COMPLEX, TIGHTLY COUPLED”

Another similarity of anesthesia to aviation industry is that both are highly
complex, dynamic, and tightly coupled. Not only are complex interactions
involved in ensuring a good outcome, but also the unpredictable

characteristics and responses of the human undergoing anesthesia make
this more difficult and need personalized planning.38,39
The term “tightly coupled” reflects the critical importance of time in the
processes, which cannot wait or stand by.40 Induction of anesthesia is a tight
time dependent process, where medication is administered followed by
paralysis and intubation. These need to be performed in quick succession.
The anesthesiologist cannot afford to be distracted, or undertake some
other task leaving patient unattended, without dire consequences. These
highly complex time coupled systems set the stage for increased likelihood
of accidents.12 Perrow suggests that these accidents, very likely to occur in
complex time coupled activities, should be viewed as inherent characteristics
of such a system, so named “normal accidents”.40
CHANGING APPROACH TO ERROR

The traditional approach to error has been to emphasize education and
training, along with punitive measures and blame apportionment as a
means of reducing errors and mitigating their effects.41 This was based on
the premise that encouraging people to be more careful and motivated
would improve safety by reducing errors. Whilst this seems obvious and
straightforward, just focusing on individuals and pushing them to perform
better has not really reduced accidents in industry analysis. The reason that
person-focused approach has not worked is because accidents are often
the result of interplay of systemic, organizational, and circumstantial factors
rather than just one unsafe worker.32
Whilst encouraging and motivating people to do better, the culture of
“naming, blaming, and shaming” the person deemed responsible deflects
from the bigger picture to actually analyze the cause of error.42 The premise
that blaming an individual for carelessness, negligence, and poor motivation
will somehow eliminate errors, is flawed.
One of the major “side effects” of this blame culture is inculcating fear,
so errors are covered up rather than admitted to. Multiple factors contribute
to this inability to acknowledge an error. The training of medical students
and doctors has been to aim for zero errors, by being extra careful and
trying hard. It follows that doctors then see themselves and their practice as
infallible, which is really a setup for trouble. When an adverse event occurs,
which is inevitable in some situations, doctors see this as a professional and
personal failure, and fear the shame that will follow when colleagues see
them as incompetent. The feelings of guilt, shame, and isolation are often
major enough for the doctor to become the “second victim”.43 It has been
said that, “..… medicine is often driven by the idea that perfection is possible
and that mistakes are a personal and professional failure. This perfection
mind-set … is laudable, admirable, and unworkable”.44
Recognition that errors are often based on complex interactions of human

behavior with equipment and procedures forms the modern approach to
understanding and addressing error. In contrast to the traditional approach,
where human cognitive limitations have been targeted, the current approach
is to accept these as the last link in events leading to adverse outcomes.
It is accepted that fatigue and long hours of work, stress, preoccupation
or distraction as well as forgetfulness can contribute to accidents, but
this is certainly not the only major or leading cause of an adverse event.32
Acceptance of inevitability of errors in some situations and acceptance of
human fallibility, besides designing and promoting safe systems is possibly
the best way to improve safety.
CAUSATION OF ERRORS ALSO MIRED IN MYTHS

Reason45 has listed some myths around error causation. These include:
• Errors are made by bad people, casting a moral shadow of karma:42 Simply
put, it suggests that people bring these bad events upon themselves, due
to performing bad actions. This is clearly a myth, given that most errors
occur to the best people performing the most difficult tasks or a good
person having a bad day.
• Errors are unpredictable and unpreventable: Another myth propagated
around error causation relates to a perception of errors being random
events, occurring without reason or warning. The reality is that errors
do occur throughout a profession.
• Highly trained individuals do not make errors: This is another myth,
negated by the fact that errors are usual and common, though most
are not associated with serious outcomes. Analysis from the aviation
industry shows only about 100 major events a year on background of
100 million errors made by flight crew.46
• Highly trained individuals make huge errors: It is commonly believed
that highly-trained professional makes huge errors invariably causing
bad outcomes. However, similar to the previous myth, statistics show
errors may be common, but serious adverse events are rare due good
preventative systems in place (e.g. alarms on anesthetic machine). Also,
individuals who are highly competent are also well trained to detect and
recover from errors before they actually cause a bad outcome.
Errors are not uniformly viewed, and like everything else, are subject to
bias. They are largely classified into outcome bias and hindsight bias.
• Outcome bias depends on adverse outcome. The worse the outcome,
the more seriously an error is viewed.47 An interesting study where 112
anesthesiologists were asked their opinion about quality of care in 21
cases showed inverse relationship between worsening outcome and
judgment of appropriate care.48 Put simply, the same set of circumstances
(in this case standard of care) was judged more critically (as being worse)
when informed that it was associated with bad outcome.
• The benefit of hindsight or retrospective analysis, once the outcome
is known, definitely alters analysis of errors and adverse outcomes.
Psychologists have studied and confirmed the phenomenon of this bias,
when those reviewing a sequence of events after the outcome can clearly
see disaster looming. On the other hand, an experienced person actually
involved in real-time management of the events may not be able to see
events unfolding in a linear fashion.12
MEDICATION ERRORS IN THE HOSPITAL

Staggering statistics from the United States show that nearly 10% of hospital
inpatient costs are attributable to potentially preventable complications,
of which medication error is a substantial contributor. Figures from 2006
estimated national healthcare costs at $940 billion, and the 9.4% contribution
from errors equates to $88 billion.49
One of the major errors encountered in health industry is that of drug
administration errors. These are estimated to account for 7,000 deaths in
the United States, and a much larger number of people suffering, along
with increase health costs.50-52 Medication errors have been documented
as the seventh most common cause of mortality in hospitalized patients,
with worst culprits being antibiotics and anesthetic agents.53 Review and
analysis of medication errors, and effective methods of prevention is one of
the strategies pursued to reduce spiraling healthcare costs as well as adverse
events.
Other studies have also substantiated the above figures relating to
costs and morbidity from medication errors. Bates et al. have analyzed
figures from a medium sized 700-bed hospital, and calculated 1 in 50 in
patients have a preventable adverse outcome related to medications. This
translates into increased hospital costs of $4,700 per admission or $2.8
million annually, which is considered preventable.54
One of the top reasons of medication error during inpatient stay is linked
to polypharmacy, given that a third of inpatients are on five or more different
medications.55 Newer medications may carry specific risks include drug
interactions, and certain groups may be more susceptible to the adverse
effects. The elderly population, with some age-related physiological changes
including reduced ability to metabolize drugs, combined with needing a
large number of medications, are at high risk of drug-related adverse
outcomes. Research has shown increased incidence of adverse events in
those over 65, possibly influenced by age-related decrease in renal function
and polypharmacy.56
The other high-risk population is young children, as drug prescriptions

need to be tightly linked to body weight. Patients with limited ability to
understand and follow instructions would also be at risk of adverse events.
A recent study showed that two-thirds of emergency hospital admission
occurred due to unintentional overdosage of certain medications. Of these,
only four groups, specifically warfarin, insulins, oral hypoglycemics, and
antiplatelet agents, accounted for 7 out of 10 emergency hospital admissions.57
Medications taken in error, if not prescribed can also result in
significant adverse events. Specific groups of medications that have this
potential include opioids, sedatives, antibiotics, potassium chloride and
hypoglycemic agents, among others. Adverse events could potentially occur
due to allergic response, even when medications are correctly administered.
This is considered to be more commonly preventable in older population
(90%) than in younger population (24%).58
CLASSIFICATION OF MEDICAL ERRORS

BASED ON IMPACT
A medication error index adopted by the National Coordinating Council for
Medication Error Reporting and Prevention (NCC MERP) in 1996 was later revised
in 2001. This index classifies errors based on impact to the patient, ranging from
whether it actually affected the patient to the degree of harm resulting in
temporary or permanent morbidity/mortality as depicted in Figure 2.
MEDICATION ERRORS SPECIFIC TO THE

PRACTICE OF ANESTHESIA
Medication errors in anesthesia are a significant contributor to morbidity
as well as mortality. Extrapolation from statistics suggests that most anes
thesiologists would be involved in at least one major error over an average
career, with about 7 errors per year.51,53 Medication errors, in association
with infusion pump problems, are reported to be the leading cause of
deaths related to anesthesia in Denmark.59 Studies from other regions
and continents have shown similar results. A prospective study of 10,000
anesthesia episodes from New Zealand showed 1 error for every 130
anesthetics administered.60 This along with some other studies listed in
Table 1 highlights incidence of drug errors. In a Canadian survey less than
70% anesthesiologists reported adhering to practice of labeling syringes and
reading labels before administration on a regular basis.61
Anesthesiologists are uniquely placed as the only subset in medical
practice to prescribe, draw up, dilute, and administer drugs and then monitor
patients for any complications. Given the high usage of medications for
induction and maintenance of anesthesia, the urgency and sometimes crisis
Fig. 2: National Coordinating Council for Medication Error Reporting and Prevention
(NCC MERP, 2001).
Source: 2014 National Coordinating Council for Medication Error Reporting and
Prevention.80
Table 1: Incidence of medication errors in key studies.

Number of
anesthetics Incidence of Percentage of
Study Study period delivered drug error drug error
Webster et al.60 Feb 1998– 10,806 81 0.75%
Oct 1999
Sakaguchi et al.65 1993–2007 64,285 50 0.078%
Llewellyn et al. 66
Jul 2005– 30,412 111 0.37%
Jan 2006
Cooper et al.70 Aug 2007– 10,574 52 0.49%
Feb 2008
Zhang et al.81 Mar 2011– 24,380 179 0.73%
Sep 2011
like situations, it is anticipated this will set the scene for errors associated
sometimes with severe adverse outcomes. An average anesthetic career
would likely involve administration of 1 million anesthetics. A significant
proportion of these would be elderly patients, presenting for high-risk
surgery, sometimes in urgent and emergency situations. Drug interactions
with medications the patients may currently be using, and failure to
recognize or reconcile these can lead to disastrous situations. Emergency
surgery and anesthesia can sometimes be dynamic and rapidly changing or
deteriorating, which demands urgent medication possibly without rechecks.
Other potential confounders are the factors that influence the patient’s
ability to tolerate any errors, including reduced physiologic reserve due to
emergency condition or trauma needing surgery, besides of course extremes
of age, and other conditions such as pregnancy.
The numbers for intensive care units appear to be a little higher with 133
medication errors reported per 1,000 patient days.62 It has been acknowledged
that a widespread pattern of under-reporting in most healthcare systems
means that the actual rate of medication errors would actually be much
higher.63 Also, given that the actual outcome of an error is influenced by
so many factors, studies need to focus and reflect on errors or near misses,
irrespective of actual outcome of harm.
As discussed, medication errors are often attributable to failure of
pathways, processes, and systems, rather than individual negligence. Lack
of protocols for administration of medications, and shortage of staff to
assists with checks and other processes are typical systemic latent causes
of medication errors. Staff shortage can also result in some practitioners
needing to work beyond reasonable hours leading to fatigue or distractions/
interruptions from attempting to manage multiple cases. Australia and New
Zealand College of Anaesthesia (ANZCA) has published statements on
fatigue and distractions, and need for safe working hours. Active causes of
failure or medication error include incorrect choice of medication or route
of administration, and failure of memory or attention.64
Studies have identified the most common medications administered
wrongly. They include vasopressors, opioids, and cardio-stimulants.65 A
study by Llewellyn66 from South Africa reported the most frequent cause of
error as being due to mislabeling of drugs. Sakaguchi also suggested that
most errors were attributable to inexperience of the practitioner involved
in drug administration.65 This issue was emphasized in many other studies,
including one by Phillips, which correlated increased errors and the start
of the new medical residents placement/rotation.67
The Journal of Patient Safety reported incorrect medication as causing
nearly half of medication errors (48%), followed by incorrect or excess
dosage (38%), and inappropriate route of administration (8%). Smaller
contributions of 4 and 2% respectively were attributable to administration

of less dosage or missing out entirely.68 The analysis further involved
breakdown of causes for administration of incorrect medication as syringe
swap in 42%, drug ampoule swap in 33%, and wrong choice of medication
in 17%. Incorrect and excess dosages were administered frequently due
to misunderstanding of dosage, wrong usage of syringe pump (21%), and
incorrect use of dilution (5%).53
Detailed breakdown of the actual process during which medication
errors are most common revealed some interesting data.69 Administration
of any medication in intensive care units involves well over a hundred little
steps, right from prescription to administration and monitoring. Though
administration is usually double-checked between two medical personnel,
it was the most common step for error (53%), far more than prescription
(17%), preparation (14%), or transcription (11%). The commonly involved
medications include heparin, potassium chloride, inotropes, and antibiotics,
which are possibly the most commonly used medications in intensive care
unit.
Analysis of medication errors in anesthetic practice70 reported events
as occurring more frequently during the maintenance phase of anesthesia
(42%) as opposed to induction (28%) or when surgery is commenced (17%).
Errors in administration of anesthetic agents could involve route or order
of administration or the actual dosage. The usual medications associated
with these errors include induction agents, anticholinergics, opioids and
neuromuscular blocking agents, among others. An impressive study by
Phillips67 also suggested similar causative factors including incorrect dose
(40.9%), incorrect medication (16%), and incorrect route (9.5%).
Another analysis of over 2,000 medication errors in anesthesia from
Australia also showed 61% events occurred during the administration
of drugs. Most commonly, it was administration of wrong drug that was
implicated, but in about 7% it was a correctly labeled syringe with wrong
drug in it. Miscommunication during provider change was identified as the
cause of error.71
An important and not uncommon cause of medication errors is
medications that have similar packaging, appearance, or labeling, but
very different pharmacological properties, as alluded to earlier. Examples
abound of medications packaged similarly with potential for confusion and
error, and anesthesia specific drugs are overrepresented in this section.
The neuromuscular blocking agents, cisatracurium and rocuronium, have
different properties including onset and duration but have similar labeling.
While mortality occurs only in a small proportion of medication
errors, the effects in many cases can be far reaching for both patients and
healthcare professionals. Increased cost to the healthcare system from
morbidity, readmission, prolonged hospital stays, lack of confidence, and
Table 2: Classification of drug errors.

Similar looking vials
Unlabeled syringes:
Drawing up drugs •• Not checking the label (including expiry date) prior to
and labeling phase administration
•• Different concentration in the syringe and incorrect label
(incorrect dilutions esp. relevant in pediatric patients)
Near misses:
•• Incorrect dose (inadequate or in excess) esp. in pediatric
patients
Drug administration Syringe swap:
phase
•• Wrong route of administration
•• Incorrect timing of administration
•• Omission, repetition, or substitution of drug
•• Adverse event not recognized or not documented
Documentation •• Reluctance among doctors to admit the error
errors
•• Failure to report an error during medication
litigation concerns in caregiver as well as damaged public perception are

all consequences of these adverse events.
Dhawan et al.72 simplified the classification (Table 2) of errors as applied
particularly to anesthesia practice.
ERROR REDUCTION AND PREVENTION—

HARM MINIMIZATION
While much work remains to be done in prevention of medication errors,
attitudes toward this are most important in determining the success of any
strategy. To this end, Ashcroft et al. studied safety culture in community
pharmacies across United Kingdom. Attitudes toward safety ranged from a
total lack of understanding for the need of any risk management strategies
to an integration of risk reduction steps in every process.73 They have
classified attitudes toward medical errors as levels 1–5, from mast dangerous
to most risk averse. Level 1 or “pathological” includes subjects who view risk
management and safety issues as a waste of time. Level 2 is more “reactive”
and responds to incidents appropriately, but actually waits for them to occur.
Level 3 or the “calculative” group tries to plan in advance and anticipate
possible scenarios. Level 4 is more “proactive” in that they are always on
the alert, understanding the inevitability of errors, if the guard is dropped.
Level 5 is “generative”, incorporating risk management strategies into every
process, and constantly working toward risk minimization.
Worldwide efforts are underway in an effort to reduce the burden of
medication errors. Bar coding of medications, reconciliation of electronic
medical records, large labels highlighting high-risk drugs, and similar

measures have been proposed and adopted in many institutions with an
aim of reducing the burden of error. The reduction in errors was modest,
and highlighted the need for finding alternative solutions to these complex
problems. Some hospitals such as Virginia Mason have drawn on industry
concepts such as Six Sigma to decrease variance and significantly improve
safety in medication administration.74
Another example of extrapolating quality concepts from industry is
demonstrable at Froedtert Hospital systems in Milwaukee.75 One main
project relating to medication errors through the intravenous route
elucidated lack of standardization as the most important cause. Six-Sigma
approach was applied to identify systems errors and then implement
methods to eliminate these errors. The causes highlighted as part of
investigation included medication orders not received, defective faxes, lack of
oversight, administration of medications on “standard” doses rather than
adjusted for weight, and continuing these medications beyond necessary
time frame.
Confirmation that errors were more often system issues and not just
individual or personal carelessness then produced system solutions.
Intravenous pumps were redesigned with up-to-date information on
preparing standard medications, based on industry approach using
Six Sigma. This will be the way forward in identifying system failures
and suggesting safety measures, though cost is usually a limiting factor. With
strong emphasis worldwide on harm minimization and risk reduction, some
strategies have been implemented. Some potential systems for safer drug
administration include but are not limited to the following:
• VEINROM: This is a novel design (still in development) for administration
of medications intraoperatively, using a predisposition syringe with
interlocking mechanism. The acronym stands for vasoconstrictors,
emergency drugs, neuromuscular blockers, induction agents, reversal
agents, opioids, and miscellaneous drugs. Ports and syringes are color-
coded. Bar code facilities allow the medication record to be updated
simultaneously with administration.76
• ValiMed: This validation of medical systems device utilizes photoelectron
spectroscopy to confirm the substance being administered when
compared with control substance. This tabletop device uses ultraviolet
(UV) light for ionization of electrons, and measures the energy of
electrons to validate the drug being administered. During an extensive
trial by Michigan health system, no drug error was reported during the
duration of trial, and also reduced wastage of drugs. Constraints include
cost and time required to run the test.77
• Robot-assisted medication preparation: With accelerated progress of

artificial intelligence and automation, robots are expected to undertake
routine tasks of drug preparation and administration. A recent report
from Italy (University of Ancona) showed no medication error after
19,000 (95%) chemotherapeutic drugs were prepared using robotic arm
aid.78
• Purchase of prefilled syringes: Some medications are being made
available in the form of prefilled syringes, and are anticipated to reduce
medication errors significantly. The industry of prefilled syringes is
projected to cross 5 billion used.79
MANAGEMENT OF ERRONEOUS
ADMINISTRATION OF MEDICATION
Medication errors in the anesthetic scenario can be associated with
significant morbidity and mortality. Preparation of premed and anesthetic
drugs with appropriate labeling prior to commencement of the case is the
first step in anesthetic management. It follows that inaccurate labeling or
identification of drugs, distraction and inexperience in a stressful operative
environment can result in errors which can sometimes be fatal. Because
some drug errors cannot be reversed, prevention is the best way to treat
and minimize errors. Terminating services of an individual who commits
an error has been commonly seen as effective prevention, though evidence
really points to identification and management of system errors.12 Methods
for prevention of errors include outsourcing of prefilled syringes, or the
cheaper option of preprinted label stickers which can be peeled and stuck
onto vials or syringes. Unlabeled vials and syringes should be compulsorily
discarded. VEINROM, ValiMed, and robotic preparation/dispensation of
medications may gain popularity once they become more affordable.
CONCLUSION
While accepting that most errors are caused by unintentional mistakes, and
are not always associated with bad outcomes, doctors need to be extremely
vigilant to avoid these errors. With efforts at prevention, it is also important
to report any near miss, so safety protocols can be further improved.
This is important in the interest of patient safety as well as reduction in
spiraling medicolegal costs. It follows that one of the principal stems in error
prevention is education of anesthesiologists regarding the unique risks of
their position. Being the only person responsible for prescribing, preparing,
and administering drugs; the onus of checking and rechecking really falls on
their shoulders. Beside this awareness and education, development of safer
and error proof systems needs to be considered as a joint venture between
anesthesiologists and their institutions. It appears that there continues to be

underreporting of medical errors, which then mask the extent and effects of
the problem. Cultural differences may contribute to difficulty in acceptance
of errors. Finally, these measures, both at individual and organizational
level, need to be accepted and implemented.
KEY POINTS
• Error is defined as an act of omission or commission in planning or
execution that contributes or could contribute to an unintended result.
• Medical errors can be classified into active errors occurring around an
incident, or latent errors that may not be immediately evident or visible.
• Multiple complex factors based on interactions of human behavior with
equipment and procedures contribute to causation of errors.
• The human factors such as fatigue, long hours of work, stress,
preoccupation or distraction as well as forgetfulness can contribute to
accidents.
• Anesthesiology is the most studied field in medicine for human factors
in accident causation. It is also identified as significantly invested in
strategies for patient safety by using technology for patient monitoring
and implementation of safety guidelines.
• Errors are not uniformly viewed, and like everything else, are subject to
outcome bias or hindsight bias.
• Most errors are potentially preventable complications which can be avoided
by education, as well as addressing underlying systemic causes.
• Medication errors have been documented as the seventh most common
cause of mortality in hospitalized patients, with worst culprits being
antibiotics and anesthetic agents.
• Errors can occur during drawing up drugs and labeling phase, drug
administration phase, or documentation phase.
• Bar coding of medications, reconciliation of electronic medical records,
large labels highlighting high-risk drugs, and similar measures have been
proposed and adopted in many institutions with an aim of reducing the
burden of error.
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CHAPTER
2 Perioperative Care of the Frail

Elderly: Current Knowledge and
Future Directions
Asha Tyagi, Rashmi Salhotra
INTRODUCTION
Aging is a universal, enigmatic, and complex phenomenon. A common
hypothesis for aging relates it to irreversible changes at cellular level.
Broadly, the mechanisms for aging could be divided into genomic instability
and damage, senescence and stem cell exhaustion, along with altered
intercellular communications.1
WHO IS AN OLD PATIENT?

An adult more than 65 years of age is defined as an elderly;2 and more than
90 years as the oldest old.3 Average life expectancy in India is 67.4 years for
males and 70.3 year for females as per the latest figures released by World
Health Organization (WHO) in 2018.4 This positive change in life-expectancy
has also manifested in an increasing number of elderly/older patients being
encountered in operating room for various surgical interventions.5 In the
USA, more than 40% of surgical patients are aged >65 years.6,7 The increased
frequency of old/elderly in clinical practice has resulted in a change in
perspective of healthcare personnel for these patients.
It is long been accepted that age-related reduction in organ reserves and
increase in comorbid conditions confers a challenge to the anesthesiologists
during the perioperative period. Both these factors are well documented,
and clinically accepted as special concerns in the elderly. However, of late
much emphasis is laid on “frailty” amongst elderly surgical patients as a
specific concern.
WHAT IS FRAILTY?
A salient question in elderly patients is whether the surgical outcome will
lead to residual disability hindering a return to preoperative functional
capacity, or lead to a prolongation of end-of-life suffering in these patients.8
To enable a scientific answer to the above question, it is best to view the
elderly as a heterogeneous population. The only unifying characteristic is
Perioperative Care of the Frail Elderly 23
perhaps their increased chronological age beyond 65 years. Elderlies could

be represented by an active octogenarian who is free from any major disease,
freely ambulant, and independently capable of tending to life on one hand;
and a younger septuagenarian on the other who is frail and dependent
on others for routine activities whether within home or in assisted living
facility, despite even a lack of obvious comorbidities. This concept of “fit”
versus “frail” elderly was promulgated as long back as 1988.9
“Frailty” also leads way to differentiation between chronological and
biological age of an old patient in clinical practice. Frailty was thus a concept
of “phenotype”2 defined essentially on the basis of functional and social
factors. It is now known that frailty is contributed toward by psychological
and physiological factors as well.
Over time the concept of frailty has been dwelled upon in greater
details. It has come to represent a decreased capacity to adapt to changes
in external or internal environment; including to physiological stressors
presented during perioperative period.2,9 Frailty is accompanied by cycles
of self-perpetuating precipitating events also.10 These cycles prevent
maintenance or regaining of homeostasis after a destabilizing event.11 The
destabilizing events go much farther than the actual surgery to include even
apparently innocuous ones such as fasting, opioids, pain, and postoperative
immobility.12
It is important to dissociate frailty from age and medical illnesses. Not all
frail patients are elderly or with medical illnesses. Similarly, not all elderly or
those with medical illnesses are frail. However, mostly frailty is witnessed in
elderly, with >20% incidence in those more than 80 years.2 The prevalence
increases with age—approximately 26% population over 85 years,13 and
33% over 90 years fit into the frailty criteria.14 These age-related figures for
incidence of frailty are mostly derived from community-based populations
and not in surgical patients per se.
HOW TO RECOGNIZE FRAILTY?

Frailty conceptualization has moved beyond the subjective impression
of a “weak” patient. There are several scores promulgated to identify and
quantify frailty, although more commonly in medical patients. More than 30
assessment tools have been identified.15 For surgical patients, the relevant
and easily applicable ones have been reviewed.1
It is important to understand that the methods can be classified into
either “clinical phenotype” or “deficit accumulation” type.
The prototype of the “phenotype method” is index given by Fried et al.16
This classical phenotype method is based on the presence (or absence) of
five criteria—(1) unintentional weight loss or shrinkage (>4.5 kg in the last
year), (2) poor endurance or exhaustion, (3) slowness in walking, (4) low
activity (<383 kcal/wk for males and <270 kcal/wk for females), and (5) a
weakness in grip strength.16 Frailty is present, if 3 or more of the criteria
are seen, depicted by an equivalent score; and prefrailty by a score of 1
or 2. The method remains one of the popular ones for its simplicity and
familiarity. The disadvantage, however, is the undue emphasis on muscle
mass (sarcopenia) with total lack for cognitive or mood assessment.
The “deficit accumulation” models are based on the theory that there
is age-related accumulation of deficits in the physiological functions, and
consequent reduction in reserves in the body organs.17 These processes of
accumulation of molecular damage are an on-going aging process, which
when present beyond a certain deficit manifest as frailty.11 Accordingly,
frailty can be measured as the number of deficits accumulated. A central
example of deficit accumulation model is the frailty index.18 The frailty index
is calculated on basis of presence of 92 variables that include symptoms,
laboratory parameters, disability indicators, or comorbidities. It is derived
mathematically as the number of variables present divided by 92. The biggest
attraction of deficit accumulation score is the lack of requirement of detailed
physical examination. However, consequent to the extremely large number
of variables included in the index several modifications with lesser variables
have been formulated. These are simpler and more user friendly. One of
the most common modifications in frailty index was made by incorporating
data from the National Surgical Quality Improvement Program (NSQIP).19
Herein, only 11 variables/deficits were included.
Some other commonly used scores for frailty in medical patients/elderly
include the following.
Edmonton Frail Scale (EFS) is a frailty scoring system based upon
cognition, general health status, functional independence, social support,
medication use, nutrition, mood, continence, and functional performance.
The maximum score for each parameter varies between 1 or 2, while the
total maximum score is 17. If the score is between 0 and 5, the patient does
not fall into the category of frail. A score of 6–7 indicates vulnerability, 8–9
is mild, 10–11 is moderate, and 12–17 is severe frailty.20
A modified version of the EFS is the Reported Edmonton Frail Scale
(REFS). The REFS assesses all the above except functional performance
which has been replaced with reported performance. The maximum score
is 18. A score between 0 and 5 indicates no frailty, 6–7 indicates apparent
vulnerability, 8–9 is mild, 10–11 is moderate, and 12–18 is severe frailty.
In addition to scores using constellation of various indicators, frailty
has been measured using single parameters also. Most commonly used
ones include the gait speed and handgrip strength.21,22 Although not as
widely validated as the Fried index or frailty index, they do correlate with
postoperative outcome. Sarcopenia is another measure of perioperative risk
in geriatric population. It refers to loss of psoas or total abdominal muscle
area as assessed on computed tomography scan and loss of functionality

assessed by the hand grip strength. The presence of sarcopenia correlates
with increased risk of morbidity and mortality.23,24
Over time, frailty has evolved as a concept with several ramifications. In
a previous publication dealing with outcome after hip fractures in elderly,
it was indicated by presence of any one of: age > 90 years (oldest old),
several comorbidities, or new acute medical condition.3 These criteria were
accepted against the background of frailty being defined as a vulnerability
to confront an acute stress such as hip fracture.
PATHOPHYSIOLOGY OF FRAILTY
Frailty is not a specific disease or disorder. It is a nonspecific constellation
of symptoms at best. Not surprisingly then, insights into its pathophysiology
also show nonspecific alterations in frail patients. These have included
alterations in inflammatory, endocrine, and immunologic markers; along
with emphasis on excessive oxidative stress.14,25 Raised C-reactive protein,
interleukin-6, neutrophils, monocytes, along with insulin resistance and
decreased testosterone have been shown in frail patients.26,27 But whether
these are merely indicators of frailty or causative reason is not known.
RISK FACTORS FOR FRAILTY

The risk factors for frailty can be categorized into social, demographic,
psychological, physiological, and most importantly functional.
Functional Factors
Functionality could be adversely affected by presence of comorbidities, even
if asymptomatic. Stroke, diabetes mellitus, arthritis, etc. are strong indicators
for development of frailty. These predispose to frailty by enhancing aging
process, decreasing mobility, or increasing inflammatory processes. Besides
comorbidities, disability also leads to frailty. Disability is best quantified in
terms of inability to carry out activities of daily life. These activities can be
divided into basic or instrumental ones. Basic activities of daily life involve
simplest tasks such as dressing up or showering while instrumental are more
complex such as driving. It is important to conceptualize that disability is a
result as well as cause of frailty.
Physiological Factors
Aging is a complex and incompletely understood phenomenon. Irrespective
of its complexity, it is a risk factor for frailty, the leading reason being a
decline in functional reserve of all organ systems.
Psychological Factors
Depression and frailty have a strong association, although the cause-
effect relation remains elusive. Depression could lower the nutritional
intake, mobility as well as muscle mass leading to frailty. At the same time
phenotype of frailty could lead to depression.
Demographic and Social Factors

Females are more prone to frailty, especially from lower socioeconomic
strata. The reason is not well proven but lesser muscle mass as compared
to males is frequently blamed. Lower socioeconomic classes may also suffer
from greater comorbidities, though not the diseases of affluence.
IMPLICATIONS OF FRAILTY
Since frailty causes decreased capacity to respond to perioperative stress,
it could be an important predictor for surgical outcomes. Indeed, evidence
shows that frailty is associated with increased 30-day postoperative
complication rate, length of hospital stay and costs, discharge to assisted/
supported living as well as mortality.14 The literature evaluating correlation
of frailty with surgical outcome is ample but remains highly heterogeneous
with regards to assessment tool of the former, and the outcome measures
evaluated.12 This has negated formulation of a meta-analysis. A recent
systematic review in patients >75 years also showed an increase in mortality
with frailty (OR: 1.1–4.97).28 A significant decline in functional capacity,
length of stay, and quality of life was also seen with frailty in surgical
patients.28 In medical patients, frailty predicts different outcome measures
such as increased incidence of falls, delirium, and general morbidity.14
Thus, frailty should be a factor for stratifying perioperative risk, and
optimizing the outcome by specific interventions. Risk stratification may
help in deciding whether surgery would be beneficial at all when keeping
in mind a holistic picture. It can also help to counsel the patient for
perioperative course. For optimization of outcome, there is a relative lack
of preferred interventions in these patients that could decrease the risk.12
“FRAIL BODY” OR “FRAIL ORGAN SYSTEM”

The concept of frailty evolved while considering the entire human body. In
recent times, frailty of a specific organ system, most commonly the heart,
has also been conceptualized. The physiological changes in various organ
systems due to aging are often elaborated upon in several standard texts.
However, there is scanty mention of their association with frailty. Below is
a brief recapitulation of only the salient changes in certain organ systems
where specific implication with frailty is also known.
Cardiovascular System
In elderlies, there is decreased contractility, increased myocardial stiffness
translating to increased ventricular filling pressures and impaired diastolic
filling. Diastolic dysfunction is thus a common finding on echocardiography.
There may also be coexisting systolic dysfunction. In the aorta, there is a
loss of elasticity and increased stiffness that gets manifested as an elevated
mean arterial pressure and increased pulse pressure.29 Pulmonary arterial
pressures may be raised as well. Additionally, there is a decreased response
to β-receptor stimulation, making the elderly patients unable to increase
the heart rate during stress. In frail elderlies, increased left atrial volume,
decreased stroke volume index, and raised pulmonary artery systolic
pressure were noted while no differences in ejection fraction or cardiac
index were noted as compared to nonfrail group, after adjusting for age
and comorbidities.30 An increased incidence of heart failure and decreased
response of heart rate to postural change also occur in frail patients.31 In
patients with heart failure, presence of frailty is associated with significantly
worse outcomes.32 In addition, heart failure mimics the nonspecific
symptoms such as fatigue and breathlessness seen with frailty that could
confound the diagnosis.
Respiratory System
Elderly patients have impaired ventilatory response to hypoxia and
hypercapnia. There is a loss of elastic recoil of lung with early collapse of the
small airways on exhalation. Increased closing capacity leads to increased
ventilation perfusion mismatch and raised shunt fraction. There is increased
anatomical dead space as well, and decreased diffusing capacity. What is
worrisome in elderlies is the strong two-way association between respiratory
impairment and frailty.33 Presence of either is associated with an increased
occurrence of the other. The nature of respiratory impairment includes both
airflow limitation as well as restrictive defect.
Nervous System
Progressive loss of gray matter occurs as a result of neuronal shrinkage and
to a lesser extent because of neuronal loss. Ventricular volume is increased.
There is a reduction in the area of epidural space, number of myelinated
fibers, inter-Schwann cell distance, and conduction velocity, making these
patients highly sensitive to the neuraxial and peripheral nerve blocks.34
Memory loss, restriction in activities of daily living (ADL), is also frequently
encountered. The elderly patients are more susceptible to sedatives and
hypnotics. Pain threshold is elevated. Dementia and Alzheimer’s disease are
dreadful problems that are commonly encountered in the patients coming
for surgery. Postoperative cognitive dysfunction (POCD) is a major concern

in this subgroup of patients. Frailty is associated temporally with cognitive
impairment and dementia in the long-term.35 In hospitalized elderlies also,
there was an increased incidence of delirium (OR: 8.5; 95% CI: 4.8–14.8) as
well as cognitive dysfunction (HR: 1.63; 95% CI: 1.27–2.08) with presence
of frailty.36,37
Musculoskeletal System
With increase in age, the muscle mass is replaced with fatty tissue and there
is a decrease in total body water. The distinctive feature of frailty is sarcopenia
(exaggerated loss of muscle mass). As a result, the consequences of muscle
mass loss will be more extensive. Volume of distribution of hydrophilic
drugs is reduced resulting in higher peak plasma concentrations. On the
other hand, the reservoir of lipophilic drugs is increased. This translates into
reduced clearance and prolonged duration of action for lipid soluble drugs
such as benzodiazepines, narcotics, sedatives, and volatile anesthetics.
SHOULD PREOPERATIVE ASSESSMENT FOCUS

ON FRAILTY ONLY?
The association of frailty with poor surgical outcome cannot be negated. Its
importance for preoperative assessment and optimization is reflected by
inclusion in the guidelines for optimal preoperative assessment of geriatric
surgical patients by the American National Surgical Quality Improvement
Program (NSQIP).38
However, the search and focus on frailty cannot shift attention from the
optimization of all aspects of the patient. A multidomain evaluation such
as the Comprehensive Geriatric Assessment (CGA), along with inclusion of
functional capacity, offers a more holistic approach to improve outcome. The
CGA can be led by a geriatrician who then coordinates with the surgeon, e.g.
in the proactive care of older people undergoing surgery (POPS) program.39
At the same time, there is no evidence to show that frailty can be
attenuated or reversed. Assessment and intervention are based on the hope
of improvement or optimization of coexisting or causative abnormalities.
ANESTHESIA IN THE FRAIL ELDERLY

Preoperative Assessment and Optimization
Specific to frailty, a concentrated preoperative exercise regimen aiming
for resistive training can increase physical functions. However, its
implementation as a focused, intensive “prehabilitation” program is
associated with feasibility and cost issues; and remains debatable.1 Even so,
prehabilitation defined as preoperative enhancement of patient condition

with the aim to improve postoperative outcome is mentioned for frail
elderlies. Dedicated preoperative programs such as POPS have shown to
improve postoperative outcomes in high-risk elderlies, though not frail ones
specifically.40 It involves identification of preoperative medical problems
and geriatric syndromes, followed by postoperative education programs
and multidisciplinary care led by POPS physician.
Anesthetic Technique
No special techniques are advocated for the frail elderly. What is
emphasized and logically required is a heightened perioperative care, after
due consideration to the decreased physiological reserve and vulnerability
to even trivial perioperative insults.
The technique will depend on nature of surgery, comorbidities and
should then be tailored individually. Emphasis during entire perioperative
period should be on prevention of complications.
One concern that could be extrapolated to frail elderlies relates to the
depth of anesthesia. Presence of the “triple low state”, i.e. low mean arterial
pressure, low minimum alveolar concentration of inhalational agent, and
low bispectral index (BIS) is shown to increase postoperative mortality.41
Independently also, an intraoperatively low BIS of <45 correlated with
increased mortality, myocardial infarction, and POCD.42 Thus excessive
sedation or depth of anesthesia should be desisted against in frail elderlies
with concentrated effort for optimization instead.
In postoperative period, special concern should be addressed toward
cognitive function, mobility, analgesia and nutrition amongst other routine
care.11
Anesthetic Drugs in Frail Elderly

There is no specific literature assessing effects of anesthetic drugs in frail
elderly. But the well-documented organ function decline in elderly would
be seen in these patients too, albeit only of greater magnitude. The usual
implications such as altered pharmacodynamics and pharmacokinetics
would be thus seen.
Postoperative Care
Frail patients are limited by physical deconditioning. The postoperative
immobility poses a risk for further rapid deconditioning. Hence, imple
mentation of the enhanced recovery pathway programs would be beneficial
in this group of patients also. Improved outcomes are proven with enhanced
recovery pathways, though not specifically for frail patients.
INTERVENTIONS TO IMPROVE OR MODIFY

OUTCOME IN FRAILTY
The type of intervention to improve outcome in frailty depends upon its
pattern. The following interventions have been tried, though not specifically
for the surgical frail patient. Almost all interventional modalities in frail
patients have been tried, but none has found equivocal usage or level I
evidence.43
Aerobic exercise improves the maximal oxygen uptake and increases
the muscle mass.44 Resistance exercise training improves the strength,
gait speed, and the distances in 6-minute walk test.45 A combination of
resistance and aerobic exercises has been found to reduce the risk of falls.46
Resistance training has also been found to be associated with a reduced
ADL disability.44 Exercise along with diet therapy has been found more
beneficial than exercise or diet alone.47
Supplementation with dehydroepiandrosterone,48 testosterone, calcium,
and cholecalciferol has been shown to improve bone mineral density but
no increase in strength or physical performance.49 Nutritional problems can
be corrected by referring to a dietician for a diet plan, educating about a
healthy diet, incorporation of micronutrients, vitamins, and minerals.
Encouraging social interactions and participation in home and
community also improve the mental and social well-being. Provision
of hearing aid, vision aids like glasses, and measures to reduce falls like
strengthening the muscles by regular exercises tailored for individuals are
simple yet effective interventions.
For patients on multiple medications and antidepressants, a medication
review and specific interventions to improve compliance toward medicine
intake can improve the frailty.
CONCLUSION
Despite a high prevalence of frailty in elderlies, there is very little formal
diagnosis or management dictated by its presence. This is despite its
association with increased postoperative mortality and morbidity. A
greater awareness and formal documentation of frailty are required for
further research aiming at improving outcome of these patients. Research
should focus on outcome of various interventions in frail surgical patients.
These interventions should include variations of anesthetic techniques and
drugs. With a plethora of assessment tools being available, it is time for
standardization of the assessment.
Increasing focus on frailty can lead to neglect of other factors such as
cognitive or neurological functions affecting the outcome. Thus it is important
to view frailty only as an additional risk factor, that may be modifiable, and
aim to use it for decisions and perioperative interventions to optimize surgical
outcome. Need of the hour could be an amalgamated score of frailty along

with other risk factors in elderlies, aiming for a comprehensive evaluation.
For the same reason, further studies should address a complementary/
supplementary role of frailty assessment to routine clinical risk stratification
[such as the American Society of Anesthesiologists (ASA)].
KEY POINTS
• Frailty, irrespective of age, is defined as a decreased capacity to adapt
to changes in external or internal environment.
• Frailty assessment in elderlies is advocated preoperatively and several
methods for the same are available.
• It is associated with adverse perioperative surgical outcomes, including
increased mortality.
• Perioperative care must be specifically designed in frail patients, aiming
to optimize the modifiable factors.
• “Prehabilitation” as part of a more extensive perioperative care plan for
elderly surgical patients may serve to improve outcome.
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of the geriatric surgical patient: a best practices guideline from the American
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American Geriatrics Society. J Am Coll Surg. 2012;215(4):453-66.
39. Harari D, Hopper A, Dhesi J, et al. Proactive care of older people undergoing
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Ageing. 2007;36(2):190-6.
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41. Sessler DI, Sigl JC, Kelley SD, et al. Hospital stay and mortality are increased in
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low minimum alveolar concentration of volatile anesthesia. Anesthesiology.
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47. Villareal DT, Chode S, Parimi N, et al. Weight loss, exercise, or both and physical
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48. Kenny AM, Boxer RS, Kleppinger A, et al. Dehydroepiandrosterone combined
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CHAPTER
3 Pregnancy-induced
Hypertension: An Update
CK Dua
INTRODUCTION
Pregnancy-induced hypertension (PIH) is a range of disorders collectively
and formerly known as toxemias of pregnancy. It is one of the common
causes of peripartum as well as perinatal morbidity and mortality. The
incidence of PIH is 10% of pregnancies worldwide.1 Yearly mortality of
severe pre-eclampsia and eclampsia is approximately 63,000.2 In India, the
incidence of hypertensive disorders in pregnancy was found to be 7.4%,
with pre-eclampsia in 5.4% of population studied.3
Incidence of PIH has increased over the years. This may be due to
late childbearing in developed countries and inadequate prenatal care
in developing countries. PIH includes gestational hypertension, chronic
hypertension, pre-eclampsia-eclampsia, and pre-eclampsia-eclampsia
superimposed on chronic hypertension.
Pre-eclampsia is a multiorgan disease that may be further complicated
by eclampsia and hemolysis, elevated liver enzymes, and low platelets
(HELLP) syndrome. There has been a significant advancement in the
pathogenesis, diagnosis, risk predictors, complications, and management
of pre-eclampsia. This has helped to improve the diagnosis, peripartum
management, and intensive care of both mother and fetus. Early onset
of severe pre-eclampsia has been associated with long-term effects in
mother as well as the child. Anesthesiologists have a challenging role in
the management of patients with severe pre-eclampsia and its variants.
They are involved in the management of convulsions, acute hypertensive
crisis, pain relief during vaginal delivery, anesthesia for cesarean delivery,
and intensive care unit (ICU) care. This chapter presents the current
classification and definition of PIH and recent advancements in diagnosis,
prediction, prophylaxis, and management of pre-eclampsia and its variants.
CLASSIFICATION OF PREGNANCY-INDUCED
HYPERTENSION
Various societies have classified and defined PIH with some variations.
American College of Obstetricians and Gynecologists (ACOG) Task Force on
Pregnancy-induced Hypertension: An Update 35
Hypertension in Pregnancy has classified PIH into chronic hypertension,

gestational hypertension, pre-eclampsia/eclampsia, and pre-eclampsia/
eclampsia superimposed on chronic hypertension.1
International Society for The Study of Hypertension in Pregnancy (ISSHP)
has classified hypertensive disorders of pregnancy into chronic hypertension,
gestational hypertension, pre-eclampsia de novo or superimposed on
chronic hypertension, and white coat hypertension.4
DEFINITION OF PREGNANCY-INDUCED
HYPERTENSION DISORDERS
Gestational Hypertension
It is characterized by the hypertension with a systolic blood pressure of
more than/equal to 140 mm Hg and/or diastolic blood pressure (DBP) of
more than/equal to 90 mm Hg. It develops for the first time after 20 weeks
of pregnancy and is not associated with proteinuria or other signs of pre-
eclampsia. It resolves by 12 weeks after delivery. It commonly develops
after 37 weeks of pregnancy. Its diagnosis is usually made postdelivery by
exclusion. Incidence in the United States is 2–3%.1,5
Chronic Hypertension
It is characterized by the hypertension that was present even before pregnancy
or develops before 20 weeks of pregnancy. The systolic blood pressure is more
than/equal to 140 mm Hg and/or DPB is more than/equal to 90 mm Hg. It
is not accompanied with proteinuria or other signs and symptoms of pre-
eclampsia. It does not resolve after delivery. Its incidence is 5%.1,5
Pre-eclampsia Superimposed on Chronic Hypertension

Of patients with chronic hypertension 20–40% develops pre-eclampsia. The
risk of complications is highest with this category of hypertension in mother
as well as the fetus and neonate.1,5
Pre-eclampsia
It is the hypertension with proteinuria which develops for the first time after
20 weeks of pregnancy. Its incidence is 2–8% worldwide. Blood pressure is
taken twice at an interval of 4 hours with the parturient at rest. Hypertension
is characterized by systolic blood pressure of more than/equal to 140 mm Hg
and/or DPB of more than equal to 90 mm Hg. Proteinuria is characterized
by the presence of ≥ 300 mg of protein in 24 hours urine collection or urine
protein creatinine ratio of ≥ 0.3 or 1+ protein on a urine dipstick.
Table 1: Diagnostic criteria for severe pre-eclampsia.1,6

Severe hypertension SBP: ≥160 mm Hg DBP: ≥110 mm Hg
CNS symptoms Cerebral or visual disturbances appear for the first time
Respiratory symptoms Presence of pulmonary edema
Thrombocytopenia Platelet count is less than 100,000/mm3
Renal dysfunction Urine output ≤ 500 mL/24 hour or serum creatinine
>1.1 mg/dL or ≥ twice the baseline value
Hepatic dysfunction Epigastric pain and or right upper quadrant pain
Liver enzymes are raised to twice the normal values
(CNS: central nervous system; DBP: diastolic blood pressure; SBP: systolic blood
pressure)
Its definition was revised in 2014. Now proteinuria is not considered

essential for the diagnosis of pre-eclampsia. Instead the presence of
hypertension with new development of thrombocytopenia, renal dysfunction
(raised serum creatinine levels), hepatic dysfunction (elevated serum
transaminases), pulmonary edema, neurological and visual disturbances,
and fetal growth restriction is diagnostic of pre-eclampsia even in the
absence of proteinuria. Pre-eclampsia may be mild or severe in nature.
Table 1 lists the diagnostic criteria for severe pre-eclampsia.
Therefore, while defining pre-eclampsia it is important to remember that:
• Edema as a criterion had been excluded earlier from the definition of
pre-eclampsia since it lacked specificity.
• The diagnosis of pre-eclampsia can now be made even in the absence
of proteinuria.1,6
• Severe proteinuria > 5 g/24 hours and fetal growth restriction were earlier
considered as features of severe pre-eclampsia. Now they have been
excluded from the list of diagnostic markers of severe pre-eclampsia.1,6
Eclampsia
It is characterized by the occurrence of new onset of generalized convulsions
in patients fulfilling the criteria of pre-eclampsia during pregnancy, labor
or within 48 hours in the postpartum period, in the absence of any other
medical condition predisposing to convulsions. The incidence of eclampsia
has decreased over time (5–8/10,000 cases).7
HELLP Syndrome
It is a variant of pre-eclampsia with severe features of hemolysis, elevated
liver enzymes, and low platelets (< 100,000/mm3).1 It can occur antepartum
or postpartum. HELLP syndrome can lead to severe maternal complications
such as hepatic hemorrhage or rupture, acute renal failure, disseminated
intravascular coagulation (DIC), pericardial and pleural effusion, and

placental abruption resulting in high maternal mortality.
Postpartum Hypertension
It is characterized by the new onset of pre-eclampsia/eclampsia/HELLP
syndrome that occurs in the postpartum period. Late postpartum hyper
tension is defined as hypertension, usually mild, which develops in women
with normotensive gestation, in the late postpartum period from 2 weeks to
6 months. It may be the predictor of future hypertension.1
PATHOGENESIS OF PRE-ECLAMPSIA
The understanding of pathogenesis for the initiation and progression of
pre-eclampsia has significantly advanced over the years. Global maternal
endothelial cell dysfunction is the prime reason for the manifestations of
pre-eclampsia. It is still not clear regarding the factors responsible for the
same. A number of hypotheses have been proposed regarding the placental
and maternal causes for the pathogenesis of severe pre-eclampsia.
Abnormal Placentation and Maternal Response2,6-9

Abnormal placentation and failure of trophoblastic invasion lead to
incomplete spiral artery remodeling in the uterus. This results in placental
underperfusion due to undilated myometrial segments. These changes
occur early in pregnancy and there are no symptoms.2,8
Underperfused and ischemic placenta releases factors into the maternal
circulation resulting in generalized inflammation and dysfunction of
maternal endothelium. Due to maternal endothelial dysfunction, there
is an increased production of the vasoconstrictor substances such as
platelet-derived thromboxane A2 (TXA2), and the decreased production of
endothelium-derived vasodilator such as prostacyclin (PGI2) and endo
thelium derived relaxant factor (EDRF). There is also an imbalance between
ET1, the most potent vasoconstrictor, and the vasodilator nitric oxide
(NO). This imbalance between vasoconstrictors and vasodilators results in
multisystem manifestations of maternal syndrome. This stage occurs late in
pregnancy and is symptomatic.10
Genetic Factors
Incidence of pre-eclampsia is higher amongst family members and in
certain populations. It may be due to recessive genetic inheritance.2
Immunological Factors
Abnormal maternal-fetal antigen-antibody reaction between maternal
and fetoplacental tissues may be responsible for the pathogenesis of
pre-eclampsia.2
Antiangiogenic Proteins
Two antiangiogenic proteins of placental origin have now been identified.
Soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) are
increased in pre-eclampsia. Vascular endothelial growth factor (VEGF)
and placental growth factor (PIGF) are antagonized by sFlt-1 resulting in
dysfunction of maternal endothelial blood vessels.11 Cigarette smoking,
which is considered to be a low risk factor, is associated with lower maternal
sFlt-1 levels.12 sEng is elevated in cases of HELLP syndrome.13 Studies have
reported that pre-eclamptic women with an increased ratio of sFlt-1-PIGF
have adverse maternal and fetal outcome compared to the parturients with
ratios of less than equal to 38.14,15
Based on pathogenesis, pre-eclampsia has been categorized into two
broad categories:
1. Placental or early onset (<34 weeks of gestation) pre-eclampsia begins
with abnormal placentation. The risk of both maternal and fetal
complications is significantly high.
2. Maternal or late onset pre-eclampsia (>34 weeks of gestation) is due to
the interaction between normal placenta and a woman predisposed to
the disease.
Most of these patients have elements of both pathologies.
Despite new advances, the pathogenesis of pre-eclampsia remains
complex.8
RISK PREDICTION AND PROPHYLAXIS OF

PRE-ECLAMPSIA
Prophylactic aspirin therapy has been recommended in parturients with
high and moderate risk factors for pre-eclampsia. The US Preventive Services
Task Force16 and The National Institute for Health and Care Excellence
(NICE)17 have identified certain maternal risk factors for pre-eclampsia
which are listed in Table 2.
• Vitamin D deficiency: It has been reported by some of the studies as a
risk factor for development of pre-eclampsia.18 However, other studies
did not report any difference with low vitamin D levels.19
• Calcium deficiency: Some of the studies observed that low serum
calcium level due to low dietary intake is a risk factor for pre-eclampsia.
They further observed that by supplementing high doses of calcium in
pre-eclamptic women with calcium deficiency, the incidence of pre-
eclampsia could be reduced.20 However, another study did not find any
significant difference.21
• Glycosylated fibronectin (GlyFn) serum levels: It has been reported to
be a risk predictor for the development of pre-eclampsia. Its levels
Table 2: Risk factors for pre-eclampsia.2,16,17

High-risk factors Moderate-risk factors
•• PIH in previous pregnancy, which •• History of pre-eclampsia in mother/sister
was associated with maternal or •• History of low birth weight baby and/
fetal complications or adverse outcome in the previous
•• Chronic hypertension pregnancy
•• Multifetal gestation •• Nulliparity
•• > 10 years pregnancy interval
•• Chronic renal disease •• Age <20 years or 35–40 years
•• Pregestational diabetes type 1 •• Obesity (BMI ≥35 kg/m2)
and 2
•• Autoimmune disorders •• Demographic characteristics
•• SLE •• African-American origin
•• Antiphospholipid syndrome •• Low socioeconomical status
(BMI: body mass index; PIH: pregnancy-induced hypertension; SLE: systemic lupus
erythematosus)
are significantly higher in parturients with pre-eclampsia throughout

pregnancy. Its clinical utility as a risk factor in the first trimester needs
more studies.22
• sFlt-1 concentrations and sFlt-1: PIGF ratio may be used as a risk
predictor for the development of pre-eclampsia. It may assist in the
risk stratification as well as timely diagnosis of pre-eclampsia, thereby
improving the maternal and perinatal outcome.15,23
• Angiogenic biomarkers as effective risk predictors and for diagnosis of
pre-eclampsia is an emerging field.14,15
Prophylactic Therapy for High-risk Patients

Aspirin therapy reduces the risk of pre-eclampsia by reducing the
thromboxane formation. As reported by Cochrane database analysis,
early administration of prophylactic low dose aspirin before 16 weeks in
parturients at high risk of developing pre-eclampsia resulted in reduction
of its incidence. There was also reduced incidence of premature birth
and perinatal mortality.24 A randomized study was conducted in high-risk
parturients to study the influence of high-dose aspirin (150 mg/day) from
11 to 14 weeks until 36 weeks of pregnancy. The incidence of preterm pre-
eclampsia was significantly reduced with higher doses of aspirin.25
US Preventive Services Task Force (USPSTF) recommends prophylactic
low-dose aspirin therapy (81 mg/day) in asymptomatic parturients with one
high-risk factor or two or more moderate risk factors for pre-eclampsia.
Therapy is started after 12 weeks of gestation, provided there is no
contraindication for its use in these women.16
Calcium supplementation is recommended by World Health Organization

(WHO) in parturients whose dietary intake of calcium is low.9
Antioxidant therapy with vitamin C and E given to parturients at high
risk of pre-eclampsia did not have any beneficial effect.26
SYSTEMIC MANIFESTATIONS OF
SEVERE PRE-ECLAMPSIA
Severe pre-eclampsia affects various systemic organs. These systemic mani
festations are due to widespread maternal endothelial dysfunction and
associated microangiopathy, vasoconstriction and malperfusion causing
organ dysfunction. Women with late onset (>34 weeks of gestation) pre-
eclampsia have better outcomes than early onset disease.
Cardiovascular Manifestations
There is increased vascular tone, exaggerated response to circulating
catecholamines, and vasoconstrictor influences. Systemic vascular resis
tance (SVR), left ventricular work, and blood pressure are increased.
Intravascular volume may be reduced to 40% in severe pre-eclampsia in
spite of generalized vasoconstriction and retention of sodium and water. It
leads to hemoconcentration and reduced hematocrit (HCT). Cardiac output
may be normal or increased. Overall studies have found that 80% of patients
have hyperdynamic circulation. Direct correlation between central venous
pressure (CVP) and pulmonary capillary wedge pressure (PCWP) appears
to be absent in severely pre-eclamptic patients. Volume expansion can
lead to left ventricular overloading, left ventricular failure (LVF), and
pulmonary edema. Left ventricular dysfunction and severe rise in SVR may
result in cardiogenic edema.2,6
Respiratory Manifestations
Increased vascular permeability, hypoproteinemia, decreased colloidal
osmotic pressure, and loss of intravascular fluid and protein into the
interstitium increase the risk of pulmonary edema in severely pre-eclamptic
patients. It is one of the severe complications of pre-eclampsia and may
occur even in the postpartum period.
Airway
There is edema formation in the oral, pharyngeal, and laryngeal structures.
This makes airway management difficult. Subglottic edema can cause
airway obstruction.2,6
Hematological
Thrombocytopenia occurs in 15 to 30% of pre-eclamptic women. There may
be significant effect on both the function and number of platelets. In severe
pre-eclampsia, platelet counts may fall to less than 100,000/mm3. Platelet
derived serotonin activates 5-HT2 receptors leading to platelet aggregation.
There is increased tendency toward thromboembolism.2,6
• Coagulability: Women with mild pre-eclampsia are relatively hyper
coagulable and those with severe pre-eclampsia are hypocoaguable.2,6
• Disseminated intravascular coagulation may occur in some patients with
pre-eclampsia due to activation of coagulation system.2,6
Central Nervous System Manifestations

Severe headache and hyperreflexia are warning signs of cerebral irritation.
Visual disturbances and seizures may occur due to cerebral vasospasm and
edema. Increased intracranial pressure may lead to cerebral hemorrhage
and coma. In a review of stroke cases, it was reported that systolic blood
pressure more than 160 mm Hg was a better predictor. Incidence of stroke
was found to be higher in the postpartum period.27
Renal Manifestations
Renal changes are characterized by proteinuria, reduced glomerular
filtration rate, and oliguria. Serum creatinine is increased. Hyperuricemia
was recognized as an early indicator of pre-eclampsia, however, a systematic
review did not report it.28 Acute tubular necrosis and renal failure may occur
following abruptio placentae, DIC, and hypovolemia.2,6
Hepatic Manifestations
Hepatic changes range from mild hepatocellular dysfunction to severe
changes in HELLP syndrome.2,6
Ophthalmic Manifestations
Retinal arteriolar spasm may lead to retinal edema and detachment.2,6
Uteroplacental Blood Flow

Reduced uteroplacental blood flow is responsible for increased fetal
morbidity and mortality in parturients with severe pre-eclampsia. Placental
hypoperfusion leads to intrauterine growth restriction (IUGR) and placental
abruption. Incidence of premature labor, perinatal morbidity, and mortality
is increased.2,6
Associated Complications of Severe Pre-eclampsia

Severe pre-eclampsia may be associated with eclampsia, HELLP syndrome,
and placental abruption.2,6
Long-term Implications of Pre-eclampsia

There is an increased risk of cardiovascular and cerebrovascular disease,
diabetes, renal disease, and thromboembolism later in life in both mother
and the child.29,30 In recent guidelines, it has been suggested that the history
of severe pre-eclampsia should be taken in women, to assess the risk of
cardiovascular and cerebrovascular disease.31,32
OBSTETRIC MANAGEMENT
Management of pre-eclampsia depends upon its severity of disease and
gestational age. Its management requires team work between obstetricians,
anesthesiologists, physicians, and intensivists.
Timing of Delivery
The delivery of the fetus and placenta is the only definitive management
of pre-eclampsia and should be considered for both maternal and fetal
indications. In cases of preterm severe pre-eclampsia, obstetrician has to
weigh the benefits and risks involved in relation to both mother and fetus
for immediate versus expectant delivery. Preterm delivery is associated
with prematurity and its sequele.1 ACOG1 and NICE17 have given guidelines
regarding the timing of delivery (Box 1).
Box 1: Timing of delivery.

•• ≥37 weeks gestation: Delivery should be expedited irrespective of severity of
disease.
•• <34 weeks gestation: Immediate delivery is not recommended due to the risk of
adverse neonatal outcome.
–– Expectant delivery is considered in these patients.
•• 34–37 weeks gestation: Optimum time of delivery to prevent maternal and
neonatal morbidity is not defined.
•• Expectant delivery: Immediate contraindications include:
–– Maternal: Uncontrolled severe hypertension, eclampsia, and placental
–– Abruption, DIC, HELLP syndrome, and significant renal impairment
–– Fetal: Nonviable fetus, abnormal fetal testing, and severe IUGR.
•• Immediate delivery: Immediate delivery in preterm gestation is considered only
after stabilizing the maternal status.
•• Corticosteroids: Immediate delivery is initiated 48 hours after corticosteroid
therapy. Steroids may be given even up to 36 weeks of pregnancy.
•• Expectant management: Frequent maternal and fetal surveillance is required.
(DIC: disseminated intravascular coagulation; HELLP: hemolysis, elevated liver enzy
mes, low platelet count; IUGR: intrauterine growth restriction)
Maternal and Fetal Surveillance for Expectant Delivery

• Maternal surveillance: All pre-eclamptic patients should be evaluated
for symptoms of progression of pre-eclampsia. Initial laboratory
investigations such as hemoglobin (Hb) and HCT, platelet count,
proteinuria, serum creatinine, serum transaminases, and serum uric acid
are done. Mildly pre-eclamptic patients do not require further coagulation
testing, if platelet count is >100,000/mm3. In patients with platelet count
<100,000/mm3, testing should be done for prothrombin time, partial
thromboplastin time (PTT), and fibrinogen. For placental abruption and
HELLP syndrome, further coagulation studies are required.1,2
• Fetal surveillance: Mostly, obstetricians recommend fetal movements,
nonstress testing, or biophysical profile testing. Ultrasonography may be
done as per requirement. Doppler study may be required in suspected
cases of IUGR.1,2
Route of Delivery
In all patients of PIH, the preferred route of delivery is vaginal. The obstetric
indications for cesarean delivery are the same as that of normal pregnancy.1,5
Antihypertensive Therapy
Severe hypertension must be treated to prevent maternal cerebrovascular
and myocardial events. Cerebrovascular accident is one of the serious
complications of severe pre-eclampsia. Sudden variations in maternal blood
pressure should be avoided.
• Tight control of blood pressure versus less tight control: Variable blood
pressure targets have been suggested by different societies. ACOG1
recommends treatment at blood pressure levels of ≥160/110 mm Hg for
pre-eclampsia and gestational hypertension. For chronic hypertension,
treatment should be started at 160/105 mm Hg with treatment goals
of 120–160/80–105 mm Hg. NICE17 recommends treatment at a blood
pressure >150/100 mm Hg for uncomplicated chronic hypertension,
gestational hypertension, or pre-eclampsia with treatment goals of
<150/80–100 mm Hg for pre-eclampsia or gestational hypertension
and DBP >80 mm Hg for chronic hypertension. Tight control of blood
pressure (DBP 85 mm Hg) resulted in reduced rates of severe maternal
hypertension as compared to less tight control (DBP 100 mm Hg) of blood
pressure.33 However, a Cochrane analysis reported that progression to
severe pre-eclampsia or eclampsia is not dependent on blood pressure
levels.34
• Tight control of blood pressure may be preferred in patients with severe
hypertension who are at a higher risk of developing complications.9
• Commonly used antihypertensive drugs to treat PIH include labetalol,

hydralazine, and nifedipine.
▪▪ Labetalol is now preferred as the drug of choice for severe hypertension.
It is a combined alpha and beta-adrenergic blocker and should be
avoided in asthmatic and congestive heart failure (CHF) patients. It
can be used orally as well intravenously. Initially, 20 mg of labetalol
is given intravenously as a bolus. Additional doses are administered
at intervals of 10–20 minutes as per requirement up to a total dose of
300 mg. It can also be administered by intravenous infusion titrated
to effect.2,8
▪▪ Hydralazine is also used for treatment of severe hypertension. It is a
potent and direct vasodilator. It has the disadvantage of development
of maternal tachycardia due to reflex sympathetic stimulation. It is
administered intravenously with an initial dose of 5 mg. Dose can
be repeated every 15–20 minutes to a maximum of 20 mg until
target diastolic pressure is achieved. It can also be administered by
intravenous infusion titrated to effect.2,8
▪▪ Nifedipine predominantly affects the arterial and arteriolar smooth
muscle. Although it is also short acting, intravenous labetalol and
hydralazine have been the preferred agents. Success rates for treating
severe hypertension with oral nifedipine were found to be similar
to hydralazine or labetalol by a systematic review. It was suggested
oral nifedipine is equally useful as an antihypertensive agent for
acute management of hypertension in the peripartum period.35 Same
findings have been reported by another meta-analysis.36 An initial
dose of 10 mg is given orally and can be repeated after 30 minutes.
Maintenance dose is 10–20 mg every 3–6 h. It is not clear whether
nifedipine can potentiate the effects of magnesium sulfate.37 ACOG
does not recommend the use of sublingual nifedipine.
▪▪ Sodium nitroprusside may be occasionally used in patients with severe
hypertension, if they are unresponsive to conventionally preferred
agents. An intravenous infusion of 0.3–0.5 µg/kg/min is given. It
should be given for short duration. Infusion rates should not exceed
4-µg/kg/min for more than 4 h to avoid the risk of cyanide toxicity
in the neonate.2,8
▪▪ Nitroglycerine is again mostly used for short-term treatment of severe
hypertension intraoperatively. Initially, it is administered at a rate of
5 µg/min by intravenous infusion. Infusion rate may be doubled every
5 minutes titrated to effect. Methemoglobinemia may result from
high-dose 7 µg/kg/hour.37
▪▪ Labetalol and nifedipine are better antihypertensive agents as com
pared to Hydralazine.38
Seizure Prophylaxis
• Magnesium sulfate is now the preferred agent for seizure prophylaxis in
severe pre-eclampsia as well as for control of convulsions in eclamptic
patients without producing central nervous system depression in mother
as well as neonate.39 There is no evidence of better maternal or neonatal
outcome following its use in patients with pre-eclampsia.2,40 ACOG does
not currently recommend its routine use in patients without severe
features of pre-eclampsia.1
• Mechanism of action: Magnesium sulfate produces depression of central
nervous system. It also potentiates the effects of nondepolarizing and
depolarizing muscle relaxants due to its effect on the neuromuscular
junction. It improves the uterine blood flow due to mild relaxant effect
on uterine vasculature and smooth muscle. It is a mild vasodilator and
has a mild antihypertensive effect. Magnesium sulfate easily crosses
placenta and can cause neonatal depression. Since it is excreted by
kidney, it should not be administered if urine output is inadequate, to
safeguard against magnesium toxicity.2,6
• Administration: Initially an intravenous bolus of 4–6 g is given over
15–30 minutes. Subsequently intravenous infusion of 2 g/hour is given.
Magnesium sulfate infusion is continued throughout the intrapartum
period and for 24 hours in the postpartum period. Therapeutic levels of
serum magnesium are 4–6 mEq/L.39,40
• Monitoring of magnesium therapy is essential to detect the early signs
of its toxicity. It is done by monitoring the respiration, urine output,
and patellar reflexes. In patients with significant impairment of renal
function, serum concentrations of magnesium should also be monitored.
Loss of deep tendon reflexes and ECG changes are seen at levels of 10
mEq/L, respiratory arrest occurs at 15 mEq/L and asystole appears at
20 mEq/L. Magnesium sulfate therapy should be immediately stopped
on detecting the signs of toxicity. Calcium gluconate 1 g or calcium
chloride 300 µgm is given to antagonize the effects of magnesium sulfate.
Supportive therapy is given as per requirement.2,6
Fluid Therapy
Severely pre-eclamptic patients are hypovolemic and need more fluids. At
the same time, fluid overloading in a patient with leaky capillaries increases
the risk of pulmonary edema. Fluid restriction is the usual practice in these
patients to minimize the risk of pulmonary edema unless there is maternal
hemorrhage. Fluid restriction should continue in the postoperative period
till diuresis occurs. In the absence of fluid and blood losses, 60–125 mL/
hour of ringer lactate is administered.41 Others have advised isotonic
crystalloid solutions at 100–125 mL/hour with additional requirements for
vasodilator therapy and regional anesthesia.37 Adjustments are made based

on patient’s clinical condition, HCT, and urine output. In case central,
invasive monitoring is being done, CVP measurement and PCWP can be the
guide. Colloids solutions have a limited role.42 Data on ideal fluid therapy in
severe pre-eclampsia is limited and further controlled studies are needed.42
Optimal fluid therapy in severe pre-eclampsia remains a controversial
issue.
Coagulopathy and Disseminated

Intravascular Coagulation
Blood components are given as per requirements and WHO guidelines.
Treatment of Eclampsia
If patient develops eclampsia, convulsions should be controlled immediately
with benzodiazepines followed by magnesium sulfate. Airway, oxygenation,
ventilation, and circulation are maintained and blood pressure is controlled.
Guarded fluid therapy as per requirement is given. Delivery is expedited
after maternal stabilization. After control of seizures, management is like
that of severe pre-eclampsia.2,6
ANESTHETIC MANAGEMENT OF PRE-ECLAMPSIA

Early involvement of anesthesiologist in the antenatal period allows timely
preoperative assessment, decision making regarding choice of analgesic,
anesthetic techniques, and monitoring. Mildly pre-eclamptic patients are
managed like normal pregnant women but they should be monitored for the
progression of the disease. Severely pre-eclamptic, eclamptic, and patients
with HELLP syndrome should be adequately stabilized prior to operative
and nonoperative delivery since they are critically ill.
Preanesthetic Evaluation
A detailed preanesthetic evaluation should be done to find out the severity
of pre-eclampsia, cardiovascular and pulmonary status, drug therapy, fluid
status, renal function and urine output, coagulation status, monitoring
requirements, and investigations. Aspiration prophylaxis is advised. A detailed
airway assessment should be done and is repeated as the labor progresses.
Difficult airway is anticipated in patients with severe pre-eclampsia.
NONOPERATIVE DELIVERY: LABOR ANALGESIA

In the past, there were concerns regarding the use of regional analgesia
and anesthesia in severely pre-eclamptic patients. These patients with
volume contraction and reduced placental perfusion were thought to be

at a higher risk of further deterioration due to the possibility of severe fall
in blood pressure. Excessive fluid administration for hypotension increases
the risk of developing pulmonary edema. There is also the risk of using
vasopressors. Now with the use of lower concentrations of local anesthetic
agents due to the adjuvants such as opioids, the safety of regional analgesia
and anesthesia is now well established.40
Continuous Lumbar Epidural

Continuous lumbar epidural is now the technique of choice in patients
with severe pre-eclampsia for vaginal delivery, provided there are no
contraindications to its use.43 Epidural analgesia should be administered
early. It safeguards against pain-related maternal and fetal complications,
and provides complete pain relief without the need for depressant drugs.
Sympathetic blockade improves the uteroplacental blood flow.2 Epidural
catheter can be easily and rapidly used for extending the block, if there is
need for cesarean section. General anesthesia and its associated risk are
avoided in the event of emergency cesarean section.40,44
Combined Spinal Epidural

This technique can be safely used in severe pre-eclampsia. It provides
the advantages of both the techniques. Spinal component provides the
reliability and rapidity of the block and is technically easier to perform.
Epidural catheter provides the flexibility to control the level of the block by
administering graduated volumes of local anesthetics. However, there is a
technical problem of testing the placement of epidural catheter due to the
pre-existing spinal block.2
Intravenous Opioids
Intravenous opioids may be used, if regional analgesia is contraindicated.
Patient-controlled labor analgesia with remifentanil has been effectively
used in pre-eclamptic patients.45
OPERATIVE DELIVERY: ANESTHETIC MANAGEMENT

Regional versus General Anesthesia
In severely pre-eclamptic patients, the preferred anesthetic technique is
regional anesthesia for obvious advantages. General anesthesia carries the
risk of morbidity and mortality associated with difficult intubation. Acute
rise in blood pressure due to hypertensive responses to laryngoscopy
and intubation carries the risk of intracranial hemorrhage. According to

Confidential Enquiry into Maternal and Child Health (CEMACH) report
(2003–2005), the most common cause of maternal death was found to be
intracranial hemorrhage.2 However, general anesthesia is the preferred
technique, for emergent lower segment caesarean section (LSCS) in severe
ongoing maternal hemorrhage, sustained fetal bradycardia with a reassuring
airway, severe thrombocytopenia, HELLP syndrome, and coagulopathy.44
Epidural versus Spinal Anesthesia

Epidural anesthesia is currently the safest technique of choice for operative
delivery. Hemodynamic changes are minimized because anesthetic levels
can be raised slowly by titrated doses. Epidural catheter can be inserted early
during labor and the block can be rapidly extended in case the cesarean
is required urgently. Spinal anesthesia is technically easier and has the
advantage of rapid onset, reliability, and less risk of epidural venous trauma.
Combined spinal epidural and single shot spinal anesthesia have been
relatively contraindicated for operative delivery in women with severe pre-
eclampsia. This was due to the acute fall in blood pressure following spinal
in patients with pre-existing uteroplacental insufficiency. Increased fluid
requirement following spinal as compared to epidural predisposes to fluid
overloading and pulmonary edema.
However, on the basis of more recent studies and clinical experience the
use of spinal anesthesia for cesarean section is gaining popularity in severe
pre-eclampsia. One of the studies reported that the incidence of spinal-
induced hypotension was found to be significantly lower in severely pre-
eclamptic parturients as compared to healthy parturients. Spinal-induced
hypotension is short lived and can be easily treated.46 There is no clinically
significant difference in maternal or neonatal outcome with spinal as
compared to epidural anesthesia.47
Spinal anesthesia is a reasonably safe technique available in severely
pre-eclamptic patients for emergent cesarean section, if there is no indwelling
epidural catheter or contraindication to neuraxial anesthesia. It avoids the
risk associated with emergency administration of general anesthesia.
Regional Anesthesia Considerations:

Severe Pre-eclampsia
Platelet Count and Regional
It is safe to give regional anesthesia at a platelet count of more than
100,000/mm3. Neuraxial block is contraindicated at a platelet count less
than 50,000/mm3. It was proposed that a platelet count threshold of 80,000/
mm3 is adequate for regional blocks in the absence of other risk factors.48
At platelets count of 50,000–<100,000/mm3, there is a significant reluctance

to give regional anesthesia since the clot strength rapidly declines at counts
less than 80,000/mm3. Relative merits and demerits of risk of epidural
hematoma with regional and undesirable effects of general anesthesia
will be the decisive factor. Another study suggested that at platelet counts
of 60,000 and 90,000/mm3, the anesthetic technique shall be decided by
treating anesthesiologist depending upon the urgency of LSCS.49 The trend
in the platelet count is also important, a rapidly falling count is a cause for
concern.6 Thromboelastography (TEG) may be useful to assess the overall
coagulation status.
Intravenous Fluids Prior to Regional Blocks

Fluid preloading is of less clinical relevance these days. Requirements of local
anesthetics are reduced due to the use of opioids as adjuvants. Intravenous
fluids should be infused carefully in pre-eclamptic parturients.40
Vasopressors
These should be given in small titrated doses initially for hypotension in
severe pre-eclampsia. Both ephedrine (2.5 µgm) and phenylephrine (25–50
µgm) can be used. Maternal blood pressure response should be measured
before administering a large dose. Exaggerated response is rarely a problem
with careful dosing.2
Controversy exists regarding epinephrine containing local anesthetic
solution, including the standard test dose containing epinephrine in
women with severe pre-eclampsia. An exaggerated hypertensive response
to accidental intravenous injection or excessive systemic absorption may
occur. Epidural adrenaline may also impair uterine blood flow. However,
no randomized controlled trials have been carried out and there are no
confirmed reports after long years of its clinical use.2 Ergometrine should be
avoided in severe pre-eclampsia because of the risk of acute hypertension.6
General Anesthesia Considerations:

Severe Pre-eclampsia2,6
General anesthesia is the preferred technique in severely pre-eclamptic
patients in certain situations. Anesthetic considerations are due to difficult
intubation, exaggerated hypertensive responses to laryngoscopy, intubation
and extubation, and magnesium sulfate therapy. Suggested technique for
general anesthesia is as under:
• Aspiration prophylaxis is given before induction.
• Radial arterial cannulation is done, if required for continuous blood
pressure monitoring.
• Preoxygenation and denitrogenation are done with 100% oxygen.

• Antihypertensive agents such as labetalol or alternatives are given for
attenuation of exaggerated hemodynamic response to laryngoscopy and
intubation.
• Difficult airway considerations are taken care of by rapid sequence
induction and intubation with propofol, thiopentone or etomidate,
and succinylcholine. Smaller size endotracheal tube is used and gentle
instrumentation is done.
• Postintubation and severe hypertension should be treated.
• Inhalational agents and nondepolarizing muscle relaxants are used for
maintenance of anesthesia.
• Patients on magnesium sulfate therapy should be given nondepolarizing
muscle relaxant after the signs of recovery from succinylcholine effect.
• Magnesium sulfate does not affect the single intubating dose of
succinylcholine.
• Neuromuscular monitor should be used to guide doses of nondepolarizing
muscle relaxants in patients on magnesium therapy.
• Magnesium sulfate therapy should be continued intraoperatively.
• Antihypertensives are given intraoperatively to manage severe hyper
tension.
• Fetal heart monitoring is done as per requirement of maternal and fetal
status.
• Antihypertensives are given before emergence and extubation to prevent
hypertensive response.
• Careful extubation is done to safeguard against laryngeal edema.
Intraoperative Monitoring
Non-invasive routine intraoperative monitoring includes non-invasive
blood pressure (NIBP), electrocardiograph (ECG), peripheral capillary
oxygen saturation (SpO2), end-tidal carbon dioxide (ETCO2), urine output,
and intravenous fluids. Platelets, coagulation status monitoring, and TEG
are done as per coagulation status of the patient.6
Invasive blood pressure monitoring may be required for patients on
intravenous vasodilators, refractory hypertension, difficult non-invasive
monitoring, and for frequent arterial blood gas measurements.
Invasive central hemodynamic monitoring may be required in severely
pre-eclamptic patients who develop pulmonary edema. It is one of the
serious complications of severe pre-eclampsia. CVP catheter is adequate in
selected cases for assessment and management of fluid status, administration
of vasoactive drugs, refractory hypertension, impending CHF, oliguria not
responding to fluid challenge, and pulmonary edema. Pulmonary catheters
are rarely needed.40
The use of central hemodynamic monitoring is a controversial issue.

Placement of invasive central venous catheter or pulmonary catheter is
associated with well-recognized risks.2
Bedside transesophageal echocardiography (TEE) or non-invasive
cardiac output monitor may be used, if available in severely pre-eclamptic
parturients if the fluid management is difficult or there are cardiac issues.40
Postpartum Considerations2,6
These patients can develop sustained hypertension, airway obstruction,
pulmonary edema, and renal failure in the postpartum period. Seizures
and HELLP syndrome may develop for the first time. Hence, monitoring
of blood pressure, fluid intake, SpO2, and urine output should continue
in the postpartum period. Magnesium sulfate should be continued for
24 hours. Antihypertensive therapy and pain medications are continued
postoperatively as per requirement. In HELLP syndrome, the upward trend
in the platelet count should be apparent by third postpartum day and counts
more than 100,000/mm3 may require 5–6 days.
CONCLUSION
Pregnancy-induced hypertension is a group of hypertensive disorders in
pregnancy. The management of severe pre-eclamptic patients presents a
considerable clinical challenge. Careful preanesthetic assessment; maternal
stabilization; and optimum obstetric, medical, and anesthetic management
are the key factors in successful management of women with severe pre-
eclampsia. Risks and benefits of different techniques should be weighed.
KEY POINTS
• Pregnancy-induced hypertension is a group of hypertensive disorders
including pre-eclampsia which is a multisystem disease with long-term
implications.
• Pathogenesis of pre-eclampsia is very complex and angiogenic biomarkers
for pathogenesis, risk stratification, and early diagnosis is the new area
for research.
• Severe proteinuria more than 5 g/24 hours and fetal growth restriction are
no longer considered as diagnostic markers for severe pre-eclampsia.
• Low-dose aspirin therapy is recommended after 12 weeks of pregnancy
in high-risk patients.
• Maternal stabilization and early delivery are the mainstays of managing
these patients.
• Pharmacotherapy includes magnesium sulfate to prevent and treat
seizures and labetalol and nifedipine to treat acute hypertension.
• Fluid therapy should be given judiciously to avoid both underperfusion
and overperfusion.
• Risk and benefit analysis of tight control of blood pressure versus nontight
control, immediate versus expectant delivery, and maternal safety versus
fetal safety are of paramount importance.
• Epidural analgesia and anesthesia for operative and nonoperative delivery
are the preferred technique.
• Spinal anesthesia is a preferred option in patients requiring emergent
LSCS.
• General anesthesia is indicated in patients with coagulopathy, emergent
cesarean section, fetal bradycardia, and other contraindications of regional
anesthesia.
• Careful postoperative monitoring should be done due to the risk of
seizures, pulmonary edema, cerebrovascular accidents, oliguria, and
venous thromboembolism. Eclampsia and HELLP syndrome may occur
for the first time in the postoperative period.
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for preventing pre-eclampsia: a systematic review and commentary. BJOG.
2014;121(8);951-7.
21. Holmeyr GJ, Seuc AH, Betrán AP, et al. The effect of calcium supplementation
on blood pressure in non-pregnant women with previous pre-eclampsia: An
exploratory, randomized placebo controlled study. Pregnancy Hypertension.
2015;5(4):273-9.
22. Rasanen J, Quinn MJ, Laurie A, et al. Maternal serum glycosylated fibronectin
as a point of care biomarker for assessment of preeclampsia. Am J Obset
Gynecol. 2015:212(1):82.e1-9.
23. Vatish M, Strunz-McKendry T, Hund M, et al. sFlt-1/PlGF ratio test for pre-
eclampsia: an economic assessment for the UK. Ultrasound Obstet Gynecol.
2016;48(6):765-71.
24. Duley L, Henderson-Smart DJ, Meher S, et al. Antiplatelet agents for
preventing pre-eclampsia and its complications. Cochrane Database Syst Rev.
2007;(2):CD004659.
25. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnancies at
high risk for preterm pre-eclampsia. N Engl Med. 2017;377(7):613-22.
26. Rumbold A, Duley L, Crowther CA, et al. Antioxidants for preventing
pre-eclampsia. Cochrane Database Syst Rev. 2008;(1):CD004227.
27. Martin JN, Thigpen BD, Moore RC, et al. Stroke and severe pre-eclampsia
and eclampsia: a paradigm shift focusing on systolic blood pressure. Obstet
Gynecol. 2005;105:246-54.
28. Thangaratinam S, Ismail KM, Sharp S, et al. Accuracy of serum uric acid in
predicting complications of pre-eclampsia: a systematic review. Br J Obstet
Gynaecol. 2006;113(4):369-78.
29. Williams D. Long-term complications of preeclampsia. Semin Nephrol.
2011;31(1):111-22.
30. Pauli JM, Repke JT. Preeclampsia: Short-term and Long-term Implications.
Obstet Gynecol Clin North Am. 2015;42(2):299-313.
31. Bushnell C, McCullough LD, Awad IA, et al. Guidelines for the prevention of
stroke in women: a statement for healthcare professionals from the American
Heart Association/American Stroke Association. Stroke. 2014:45(5):1545-88.
32. Behrens I, Basit S, Melbye M, et al. Risk of post-pregnancy hypertension in

women with a history of hypertensive disorders of pregnancy: nationwide
cohort study. BMJ. 2017;358:j3078.
33. Magee LA, von Dadelszen P, Ray E, et al. Less-tight versus tight control of
hypertension in pregnancy. N Engl J Med. 2015;372(5):407-17.
34. Abalos E, Duley L, Steyn DW, et al. Antihypertensive drug therapy for mild
to moderate hypertension during pregnancy. Cochrane Database Syst Rev.
2007;(1):CD002252.
35. Firoz T, Magee LA, MacDonnell K, et al. Oral antihypertensive therapy for
severe hypertension in pregnancy and postpartum; a systematic review. BJOG.
2014;121(10):1210-8.
36. Shekhar S, Gupta N, Kirubakaran R, et al. Oral nifedipine versus intravenous
labetalol for severe hypertension during pregnancy: a systematic review and
meta-analysis. BJOG. 2016;123(I):40-7.
37. Dildy GA, Michael A, Belfort M. Complications of Pre-eclampsia. In: Belfort
M, Saade G, Foley M, Phelan J, Dildy GA (Eds). Critical Care Obstetrics, 5th
edition. United States: Blackwell publishing Ltd; 2010. pp. 138-465.
38. Markham K, Funai EF. Pregnancy-related hypertension. In: Creasy RK, Resnik
R, Iams JD (eds). Creasy and Resnik’s maternal-fetal medicine, 7th edition,
Philadelphia; Elsevier; 2015. pp: 756-81.
39. Cahill AG, Macones GA, Odibo AD, et al. Management for seizure prophylaxis
in patients with mild preeclampsia. Obstet Gynecol. 2007;110(3):601-7.
40. Rudra P, Basak S, Patil D, et al. Recent advances in management of preeclampsia.
BJMP. 2011;4(3):433.
41. Anthony J, Schoeman LK. Fluid management in pre-eclampsia. Obstet Med.
2013;6:100-4.
42. Pretorius T, van Rensburg G, Dyer RA, et al. The influence of fluid management
on outcomes in preeclampsia: a systematic review and meta-analysis. Int J
Obstet Anesth. 2018;34:85-95.
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44. Ankichetty SP, Chin KJ, Chan VW, et al. Regional anesthesia in patients with
pregnancy induced hypertension. J Anaesthesiol Clin Pharmacol. 2013;29:435-44.
45. El-Kerdawy H, Farouk A. Labor analgesia in preeclampsia: remifentanil patient
controlled intravenous analgesia versus epidural analgesia. Middle East J
Anesthesiol. 2010;20:539-45.
46. Aya AG, Mangin R, Vialles N, et al. Patients with severe preeclampsia experience
less hypotension during spinal anesthesia for elective caesarean delivery
than healthy parturients: a prospective cohort comparison, Anesth Analg.
2013;97:867-72.
47. Henke VG, Bateman BT, Leffert LR. Focused review: Spinal Anesthesia in Severe
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48. Douglas M. The use of neuraxial anaesthesia in parturients with thrombo
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Med Interne. 2012;33:446-52.
Sugammadex and Beyond 55
CHAPTER
4 Sugammadex and Beyond
Vinh Nguyen, Kumar Belani
INTRODUCTION
A major advance in the clinical practice of anesthesia to improve the
reversal of steroidal nondepolarizing neuromuscular agents (NDNMA)
was introduced by the drug, sugammadex. Sugammadex is a modified
cyclodextrin, and its chemical structure was designed to from an inclusion
complex with steroidal compounds rendering the molecule inactive.
Sugammadex was modified from its parent compound to encompass all
four hydrophobic rings of the neuromuscular blocking agent (NMBA) in
its lipophilic cavity. Within the cavity, there is an electrostatic interaction
between the negatively charge acidic groups (COO–) and the positively
charge nitrogen of the NMBA. In a rocuronium-induced blockade, these
sequestration mechanisms encapsulate free floating rocuronium causing
a diffusion gradient to allow rocuronium-bound nicotinic receptor to
dissociate as free plasma and be further neutralized by sugammadex. This
process is immediate and continues to create a diffusion gradient until all
the rocuronium is uncouple from the neuromuscular junction.1
SUGAMMADEX VERSUS ANTICHOLINESTERASE

INHIBITORS
Sugammadex was first approved in the European Union in 2008 for clinical
usage and other countries followed suit.2 It had been recently approved
for clinical use in the United State of America by the Food and Drug
Administration (FDA) in 2015.3 Prior to sugammadex, the only effective
reversal agent was the anticholinesterase (AChE) inhibitors, in particular
neostigmine and pyridostigmine. Some of the disadvantage of AChE inhibitors
included their limited efficacy in reversing deep blockade, which caused the
speed of recovery to be unpredictable and a ceiling effect reached when the
AChE inhibitors are 100%. Therefore, AChE inhibitors can only be used if
the neuromuscular function returned to some degree. Numerous unwanted
adverse effects such as bradycardia and hypersalivation have been linked to
AChE inhibitors thus, a coadministration of an anticholinergic is required.
Overall, sugammadex is a new and novel reversal agent which may be the
answer to previous old problems.
Although the reversal of sugammadex is rapid, neuromonitoring is still
essential to ensure a return of motor function. Residual muscle paralysis still
remains a complication even with the use of sugammadex. Multiple case
reports of recurarization have occurred after sugammadex when it was given
to an intensive care patient postrocuronium infusion, an obese individual,
and a pediatric patient undergoing cardiac catheterization.4-6 Train of four
ratio (TOFR) should be monitored exclusively during any NDNMAs and
reversed with the appropriate dose. Patient with a deep block, no train of
four (TOF) but a post-tetanic count (PTC) of 1–2 will require 4 mg/kg–1.
Full recovery at TOF 0.9, was 17 times faster (2.7 min) than 0.07 mg/kg–1
neostigmine (49 min) at the recommended dose of 4 mg/kg–1.7 A recent
observational study reported that sugammadex was significantly faster
compared to neostigmine independent of the level of blockade, shallow
block: 2.2 versus 6.9 min and deep block: 2.7 versus 16.2 min respectively.8
Pongracz et al. looked at the appropriate dose for four twitches of TOF and
found that 1.0 mg/kg–1 was appropriate for a TOF >0.9 recovery in 2.1 min.9
Furthermore, sugammadex at 0.22 mg/kg dose effectively and comparably
reverse a rocuronium-induced shallow residual neuromuscular block at a
TOF ratio of 0.5 (Table 1).10 Currently, there is no dose recommendation
for vecuronium-induced neuromuscular block. Sugammadex affinity for
vecuronium-induced blockade is less compared to rocuronium. In fact,
sugammadex had approximately 2.5 times the affinity for rocuronium.11
Vecuronium took twice as long as rocuronium (3.0 min vs 1.5 min) after
sugammadex reversal.12 Similarly, Duvaldestin et al. showed a slow speed of
recovery of 3.3 min with vecuronium when the PTC of 1–2.13 A dose-response
Table 1: Recommended sugammadex dose to reverse rocuronium blockade.

Sugammadex Mean recovery time
dose Depth of NMBA to TOF 0.9 Studies
16 mg/kg –1
After 1.2 mg/kg–1
1.5 minutes De Boer et al.56
of rocuronium
4 mg/kg–1 Deep block, PTC 1–2 3 minutes Jones et al.7
Della Rocca et al.8
2 mg/kg–1 Moderate block, two 2 minutes Pland et al.
twitches to TOF Della Rocca et al.8
1 mg/kg–1 Four twitches to TOF 2 minutes Pongracz et al.9
0.22 mg/kg–1 TOF 0.5 2 minutes Schaller et al.10
(kg: kilogram; mg: milligram; NMBA: neuromuscular blocking agent; PTC: post-
tetanic count; TOF: train of four)
relationship between vecuronium and rocuronium at different dose of

sugammadex was done and consistently showed a slower recovery from
vecuronium.14
SPECIAL CONSIDERATIONS
Morbid Obesity
The use of NMBAs in morbidly obese patients can cause significant
postoperative complications in the recovery phase, if reversal is inadequate.
Critical respiratory events include airway obstruction, hypoventilation,
hypoxia, hypercapnia, and aspiration, and these can lead to acute
respiratory failure. Sugammadex had shown promising effect to rescue
postoperative residual recurarization after neostigmine was ineffective in
the recovery room for a morbidly obese patient.15 Patient receiving sugam
madex compared to neostigmine recovered (TOFR 0.9) three time faster,
2.7 min versus 9.6 min, respectively.16 Furthermore, patients undergoing
laparoscopic removal of adjustable gastric banding demonstrated faster
postanesthesia care parameters; improved TOFR, ability to swallow, ability
to get into bed independently, and discharge to surgical ward earlier.17 Thus,
rapid recovery from sugammadex can be beneficial for morbidly obese
patient to fast-track bariatric surgery and in ambulatory setting. Although
the reversal of NMBAs with sugammadex was faster than neostigmine,
postoperative respiratory complications had not been fully elucidated. Ezri
et al. had found no difference in the incidence of respiratory complications
but rather a higher SpO2 in the sugammadex group. Despite the statistical
difference in SpO2, its clinical importance seemed to be minimal and no
postoperative respiratory events were noted.18 There will need to be more
large, prospective, randomized trials to evaluate the benefit of sugammadex
to decrease postoperative respiratory complications in this population.
Pediatric Population
Sugammadex has been widely studied in adults but has not received FDA
approval in the pediatric population. The appropriate dose-response studies
in the pediatric group have not been well defined. The pharmacokinetic
(PK) and pharmacodynamic profile of rocuronium in infants and children
differ from adult patients. In infants and children, the clinical duration was
longer and the potency of rocuronium was greater compared to adults.
The group from Europe employed a multicenter, randomized group study
to explore the efficacy and safety in infants, children, adolescent, and
adults. When the reappearance of T2 of the TOF was seen, either placebo
or sugammadex was randomly assigned and the median recovery time to
TOF 0.9 was measured. The placebo group recovery time was 21, 19, 23.4,
and 28.5 min in infants, children, adolescents, and adults, respectively. After
2.0 mg/kg sugammadex, the TOF 0.9 was 0.6, 1.2, 1.1, and 1.2 min, respectively.
Therefore, this initial dose-response study explained the similarities in
the recovery of neuromuscular blockade between the pediatric and adult
group.19 Furthermore, a systematic review of nine studies comparing
sugammadex to neostigmine indicated that sugammadex can reverse
rocuronium-induced neuromuscular blockade more rapid with a lower
incidence of bradycardia.20 One area that sugammadex may benefit pediatric
patients was those with neuromyopathic conditions. In myotonic dystrophy
patients, reversal with neostigmine can precipitate myotonia crisis therefore
making sugammadex an attractive alternative. Sugammadex was successful
in reversing myotonic dystrophy without perioperative complications or
exacerbation.21,22 Certain other underlying conditions including Duchenne
muscular dystrophy, myotonic dystrophy, and myasthenia gravis caused the
neuromuscular junction to be highly sensitive to NMBAs and experience
residual weakness.23-25 These case reports highlighted the importance of
using sugammadex for a safe and rapid recovery from NMBAs. In another
report, the role of sugammadex was essential for airway rescue and this
needs to be entertained in the difficult airway algorithm. Woloszczuk-
Gebicka B et al. reported a case in a 9-month-old infant who fell into the
“cannot intubate-cannot ventilate” scenario. Sugammadex (8 mg/kg–1) was
administered and spontaneous ventilation was achieved within 25 sec.26
Elderly Population
The increasing number of elderly patients with comorbidities has greatly
impacted the clinical practice of anesthesia. The elderly patients are at
high risk for postoperative residual neuromuscular blockade resulting
in muscle weakness, airway obstruction, respiratory failure, hypoxemia,
atelectasis, and pneumonia. Therefore, reversal drugs are an important part
of the anesthetic practice. The use of neostigmine has reduced the risk of
residual neuromuscular blockade but has not eliminated this complication
in the recovery period. In the elderly group, the increase chronic disease
and receptor sensitivity may alter the PKs of sugammadex. McDonagh
et al. demonstrated a prolong recovery time to a TOFR 0.9 with old-elderly
patients (>75 years) compared to adults (18–64 years) 3.6 min versus 2.3 min,
respectively.27 In a recent prospective study by Yazar et al., TOF 0.9 recovery
in older elderly (greater than 75 years) versus young elderly (65–74 years)
was prolonged, 5.5 min versus 3.27 min, respectively.28 Muramatsu et al.
suggested that elderly patients were at the greatest risk for recurarization and
residual muscle paralysis when low dose sugammadex was administered.
The slower spontaneous TOFR and impaired renal function were two
major contributing factors that decreased TOFR change rate in response
to low-dose sugammadex.29 In a clinical series performed by Suzuki et al.,

a complete reversal of deep muscle paralysis using 4 mg/kg took longer
in elderly patients.30 All these studies were consistent demonstrating a
prolonged recovery in the older patient with either a moderate or deep
block. On average, the rocuronium-induced NMBA reversal is prolonged
by at least 1–2 minutes in the elderly than in young adults.
ADVERSE EFFECTS
Hypersensitivity and Anaphylaxis
The approval of sugammadex for USA was delayed until 2015 due to
hypersensitivity concerns. In general, perioperative anaphylaxis is a life-
threatening condition most commonly reported occurring with NMBAs.
Among the steroidal NMBAs, rocuronium has a higher rate of IgE-mediated
anaphylaxis.31 With the availability and widespread use of sugammadex to
encapsulate and reverse steroidal NMBA, there had been confirmed cases
of allergic anaphylactic reactions with clinical doses triggering significant
shock.32,33 However, the number of reported sugammadex-induced
anaphylaxis was much less than those associated with NMBAs. Dose-
related hypersensitivity reactions had been reported with its use. A joint
study by de Kam et al. reported hypersensitivity or anaphylaxis reactions
to sugammadex to be dose dependent. Hypersensitivity occurred in 0.7%
and 4.7% after sugammadex 4 mg/kg–1 and 16 mg/kg–1, respectively.34 The
incidence of hypersensitivity and anaphylaxis with sugammadex had a low
overall score (<1%) compared to placebo or neostigmine. The incidence
of spontaneous reports of anaphylaxis was similar in a perioperative
setting in which NMBAs had been administered. Approximately, 15–34
confirmed cases per 100,000 operations occur corresponding to a risk of
0.015–0.034%. On the other hand, sugammadex might be a novel drug to
manage rocuronium-induced hypersensitivity or anaphylaxis. Sugammadex
was used successfully to rapidly resolve the pseudo-allergic reaction as
seen during intradermal testing on three patients.35 There were several
reports that suggested the possibility of hemodynamic improvement in a
rocuronium-induced anaphylaxis by the administration of sugammadex.35-37
Whether this beneficial effect was due to the inhibition of IgE-mediated
activation of mast cells remains unknown. Despite this potential therapy
rescue by sugammadex, there had been suspicion that the sugammadex-
rocuronium inclusion complex may give rise to an allergic response. The
physical and chemical properties of a drug and its host carrier can be
altered, thus exposing certain molecule groups to be an antigen. There had
been a few reported cases of this nature via positive skin testing for the
inclusion complex while the same subjects demonstrated a negative skin
test for the individual drug of sugammadex and rocuronium.38-40 Although

sugammadex can cause hypersensitivity or anaphylaxis, its incidence was
similar to that generally observed in the perioperative suite in the setting of
NMBA use. The likelihood was greatest at higher dose and can occur within
4 min.
Myth of Anticoagulation
Preclinical in vitro studies demonstrated that sugammadex can increase
activated partial thromboplastin time (aPTT) and prothrombin time (PT).41
Two sugammadex clinical doses, 16 mg/kg–1 and 4 mg/kg–1, were analyzed
for its coagulation effects. Both caused a transient increase in aPTT and
PT but resolved quickly (<30 min).41 In a prospective observational study,
131 patients in either the 2 mg/kg–1 or 4 mg/kg–1 sugammadex groups were
tested for coagulation tests and bleeding in a clinical setting. The authors
concluded that neither groups were associated with a longer clotting
time or decreased hemoglobin concentration.42 The results obtained with
thromboelastography (TEG), however, provided a different result but only at
high blood concentrations of sugammadex. The two highest concentrations
of sugammadex 16 and 32 mg/kg–1, significantly altered all TEG parameters.
However, the therapeutic concentration of 4 mg/mg–1, did not induce any
clinical changes in any TEG parameters.43
RELATIVE CONTRAINDICATIONS AND CAUTIONS

Renal Dysfunction
Sugammadex is exclusively excreted by the kidneys in healthy volunteers
with minimal radioactive 14 C-labeled sugammadex in blood, feces, and
exhaled air.44 Trials had been done to evaluate the safety of sugammadex
on rocuronium-induced blockade in renal failure. The PK relationship of
sugammadex reflected a large difference in severe and end-stage renal
disease compared to normal renal function patients. Although the clearance
is decreased, these renally impaired patients were monitored for 48 hours
without any sign of recurarization.45 Two independent studies measured the
efficacy and safety of sugammadex in severe renal impairment after reversing
a deep neuromuscular block with 4 mg/kg–1. In the renal impairment group,
neuromuscular recovery was slower than the healthy patients and neither
of the studies demonstrated recurrence of blockade.46,47 After binding with
rocuronium, the sugammadex-rocuronium complex is highly stable. It has
a very low dissociation rate (Kd = 0.1 × 10–6 M) due to the strong binding
forces.48 As a result, the complex may remain intact in the plasma for days,
thus limiting any clinical complications or recurrence of neuromuscular
blockade. The muscle relaxant reversal is dependent on the encapsulation
by sugammadex to neutralize muscle blockade effect and not the excretion

of the complex in the urine.49 One should note, however, that the current
literature does not specify the appropriate safe use of sugammadex for
patient with creatinine clearance <30 mL/min.
Contraceptive Use
Since the FDA approval of sugammadex in 2015, multiple institutions are
changing their anesthesia consents to caution childbearing women about
the interaction of sugammadex and contraceptives. Sugammadex had been
shown to interact with progesterone, as found in progesterone only and
combined oral contraceptive preparations, vaginal rings, implants, and
intrauterine devices. A dose of 4 mg/kg–1 sugammadex had been predicted
to decrease progesterone exposure by 34%, similar to a daily oral dose
taken 12 hours too late. According to the package from Merck & Co, Inc.,
section 5.6, specified a potential lowering of the free plasma concentrations
of hormonal contraceptive. Furthermore, section 7.3 stated that a dose of
sugammadex is equivalent to missing a dose of oral contraceptives. Those
patients taking oral hormonal contraceptive must refer to the package label
and follow the directions for a missed dose. Those women using nonoral
hormonal contraceptives must be advised to use additional nonhormonal
contraceptive methods or a backup method of contraception (e.g. condoms)
for the next 7 days.
FUTURE REVERSAL AGENTS

Sugammadex has been a novel discovery in revolutionizing the reversal
of NMBAs. Over the past decade, a newer class of drug called calabadion
has been tested for anesthetic usage. This drug came from an acyclic
member of the Cucurbit[n]urils family of “molecular containers”, similar to
the cyclodextrins class of host-guest complexes. The structure contains a
central glycoluril tetramer backbone which forms a C-shaped configuration
to capture specific targets. The flexibility of the molecule allows the cavity
to expand and accommodate different drug targets of various sizes.50 Two
different cucurbiturils compounds, calabadion 1 (CB1) and calabadion 2
(CB2), have been reported to reverse both steroidal and benzylisoquinoline
NMBAs via encapsulation in the same 1:1 binding ratio as sugammadex.
Originally, the first generation CB1 was the first used to reversed deep
cisatracurium-induced NMB. The newer second-generation formulation,
CB2, was shown to have a five times higher affinity toward cisatracurium.51
Although calabadions successfully bind to benzylisoquinolines NMDAs,
they have a much lower affinity than steroidal NMBAs group. The in vitro
study of CB1 has a high affinity for rocuronium but inferiorly compared to
sugammadex. On the other hand, CB2 affinity for rocuronium was nearly
20,000 times that for acetylcholine compared to CB1, which was only 350
times that for acetylcholine.52 A head-to-head comparison of CB2 potency
to sugammadex has been established. CB2 binds rocuronium 89 times
stronger than sugammadex, as it requires a lower number of molecules to
allow a faster recovery phase compared to sugammadex.53 Since calabadions
have a more effective binding capacity for other classes of drug beside
NMBAs, they should be considered a broad-spectrum reversal agent. Unlike
sugammadex, calabadions have no coagulation inhibitory effect and lower
allergenic profile due to the lack of sugar moiety. These less adverse effects
make calabadions an idea reversal agent in the near future.
Other Novel Reversal Drugs

Gantacurium, the first isoquinolinium muscle relaxant group described
in the early 1990s, was found to have a rapid and a wide safety margin.
It was considered an ultrarapid nondepolarizer muscle blocker due to
its quick chemical degradation. Unlike cisatracurium or atracurium,
gantacurium is rapidly hydrolyzed by a nonenzymatic chemical reaction
which involves endogenous cysteine adduction. A cysteine adduction is due
to a replacement of chlorine (native gantacurium) by cysteine, which forms
a heterocyclic ring (modified gantacurium). This chemical ring formation
prevents the interaction of modified gantacurium to the neuromuscular
junction, rendering it inactive.54 Due to the fact that the drug had a poor
safety profile (histamine release and bronchospasm), gantacurium was
modified to prevent these adverse effects. An intermediate isoquinolinium
muscle relaxant group, CW002, was developed and designed to interact
more slowly with endogenous L-cysteine and degraded in the same
fashion as gantacurium. CW002, a benzylisoquinolinium fumarate diester,
was studied in human subjects with no cardiopulmonary side effects or
histamine release but rapidly reversed with L-cysteine administration.55
Exogenous L-cysteine is nontoxic and commonly administers in human as
an essential component of parenteral nutrition. In the new age of reversal
agents, sugammadex has begun a new wave of customized reversal with a
higher safety profile (Table 2).
Although the FDA has approved the use of sugammadex, the concerns
over the potential for hypersensitivity or anaphylactic reactions, bradycardia
and even asystole have made clinicians more aware of its potential adverse
effects. Therefore, this newer NMBA and its exclusive reversal using
L-cysteine may play an essential role for an emerging family of selective
relaxant binding agents with limited adverse effects.
Table 2: Summary of the new reversal agents for neuromuscular blocking drugs.
Developmental
Agents Structure Target Mechanism stage
Sugammadex Cyclodextrin Steroidal Envelops FDA approval
compounds NMBA with USA in 2015
high affinity
binding
Calabadion Acyclic All NMBAs Promote bind Not approved
Cucurbit[n]uril ing affinity to yet
NMBA and
then engulf
Cysteine Amino acid Novel Cysteine Not approved
with thiol side isoquinoliniums adduction yet
chain
(FDA: food and drug administration; NMBA: neuromuscular blocking agents; USA:
United States of America)
CONCLUSION
Sugammadex is the most recent approved drug to reverse the effect of
rocuronium. It can also, reverse vecuronium but the reversal is slower. As
a benefit, its use does not require the addition of anticholinergics. The usual
clinical dose ranged from 2 mg/kg–1 to 4 mg/kg–1 and is based upon the
TOF recovery profile. The drug has an acceptable side effect profile with a
low incidence of an allergic response. The hypersensitivity or anaphylaxis
mechanism is still undetermined but may be considered as a rescue agent
for rocuronium-induced anaphylaxis. The speed of onset of rocuronium-
induced neuromuscular block is based upon the dose of sugammadex.
Larger doses have been used successfully to rapidly reverse a strong
rocuronium-induced neuromuscular block. In the different generation
classes, pediatric patient showed similar results as adult unlike elderly
patients, sugammadex reversal is prolonged up to 2 min. The drug may
promote fast-tracking in the morbidly obese patient especially for same
day surgery. The coagulation profile was not elevated unless dose is higher
than 4 mg/kg–1 as reported with TEG. Sugammadex forms a strong bond
with rocuronium that is exclusively excreted by the kidneys. The strength
of its interaction did not demonstrate any sign of recurarization in renal
dysfunctional patient. Although the data is limited for patient with stage 4
kidney disease or higher, caution is still needed for these types of patients. In
addition, those patients who are using oral or nonoral contraceptives need
to perform abstinence or to use other forms of contraception for 7 days after
sugammadex administration. Sugammadex has been the cornerstone and
prototype for other reversible agents. The future is bright for newer reversal
agent such as calabadion, a broad spectrum NBMAs for steroidal and

benzylisoquinoline molecules. As well, exogenous L-cysteine has a unique
mechanism that promotes adduction of a new NMBA, isoquinoliniums, to
impair its function and inactive the molecule.
KEY POINTS
• Sugammadex acts by encapsulating only steroidal nondepolarizer muscular
relaxants and eliminating them as an inclusion complex via the kidneys.
• The reversal is rapid compared to anticholinesterase inhibitors thereby
limiting potential adverse outcomes.
• Clinical recovery time from sugammadex is similar in adult and children.
• In obese patients, it may improve fast recovery in an outpatient setting
but may not eliminate postoperative respiratory complications.
• In elderly patients, recovery from sugammadex is prolonged by 1–2
minutes.
• Hypersensitivity to sugammadex has the same incidence rate as other
potential drug allergens.
• Delayed blood coagulation by sugammadex has a limited effect at clinical
dose.
• Sugammadex efficacy on renal dysfunction patient is still unknown.
• Sugammadex may lower the efficacy of hormonal contraceptives because
of its interaction with progesterone.
• Calabadion is a new broad-spectrum drug that engulfs all types of
nondepolarizer muscle relaxants.
• Exogenous L-cysteine rapidly inactivates isoquinolinium type non
depolarizer.
REFERENCES
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pharmacology. Anesth Analg. 2007;104(3):575-81.
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assessment report. [online] Available from: https://www.ema.europa.eu/en/
medicines/human/EPAR/bridion [Last accessed August, 2019].
3. Thompson CA. Sugammadex approved to reverse NMBA effects. Am J Health
Syst Pharm. 2016;73(3):100.
4. Carollo DS, White WM. Postoperative Recurarization in a Pediatric Patient After
Sugammadex Reversal of Rocuronium-induced Neuromuscular Blockade: A
Case Report. A A Pract. 2019.
5. Murata T, Kubodera T, Ohbayashi M, et al. Recurarization after sugammadex
following a prolonged rocuronium infusion for induced hypothermia. Can J
Anaesth. 2013;60(5):508-9.
6. Le Corre F, Nejmeddine S, Fatahine C, et al. Recurarization after sugammadex
reversal in an obese patient. Can J Anaesth. 2011;58(10):944-7.
7. Jones RK, Caldwell JE, Brull SJ, et al. Reversal of profound rocuronium-induced
blockade with sugammadex: a randomized comparison with neostigmine.
Anesthesiology. 2008;109(5):816-24.
8. Della Rocca G, Pompei L, Pagan DEPC, et al. Reversal of rocuronium induced

neuromuscular block with sugammadex or neostigmine: a large observational
study. Acta Anaesthesiol Scand. 2013;57(9):1138-45.
9. Pongracz A, Szatmari S, Nemes R, et al. Reversal of neuromuscular blockade
with sugammadex at the reappearance of four twitches to train-of-four
stimulation. Anesthesiology. 2013;119(1):36-42.
10. Schaller SJ, Fink H, Ulm K, et al. Sugammadex and neostigmine dose-finding
study for reversal of shallow residual neuromuscular block. Anesthesiology.
2010;113(5):1054-60.
11. Bom A, Hope F, Rutherford S, et al. Preclinical pharmacology of sugammadex.
J Crit Care. 2009;24(1):29-35.
12. Puhringer FK, Gordon M, Demeyer I, et al. Sugammadex rapidly reverses
moderate rocuronium- or vecuronium-induced neuromuscular block during
sevoflurane anaesthesia: a dose-response relationship. Br J Anaesth. 2010;
105(5):610-9.
13. Duvaldestin P, Kuizenga K, Saldien V, et al. A randomized, dose-response study
of sugammadex given for the reversal of deep rocuronium- or vecuronium-
induced neuromuscular blockade under sevoflurane anesthesia. Anesth Analg.
2010;110(1):74-82.
14. Suy K, Morias K, Cammu G, et al. Effective reversal of moderate rocuronium-
or vecuronium-induced neuromuscular block with sugammadex, a selective
relaxant binding agent. Anesthesiology. 2007;106(2):283-8.
15. Carron M, Freo U, Ori C. Sugammadex for treatment of postoperative residual
curarization in a morbidly obese patient. Can J Anaesth. 2012;59(8):813-4.
16. Gaszynski T, Szewczyk T, Gaszynski W. Randomized comparison of sugammadex
and neostigmine for reversal of rocuronium-induced muscle relaxation in
morbidly obese undergoing general anaesthesia. Br J Anaesth. 2012;108(2):
236-9.
17. Carron M, Veronese S, Foletto M, et al. Sugammadex allows fast-track bariatric
surgery. Obes Surg. 2013;23(10):1558-63.
18. Ezri T, Evron S, Petrov I, et al. Residual Curarization and Postoperative
Respiratory Complications Following Laparoscopic Sleeve Gastrectomy. The
Effect of Reversal Agents: Sugammadex vs. Neostigmine. J Crit Care Med (Targu
Mures). 2015;1(2):61-7.
19. Plaud B, Meretoja O, Hofmockel R, et al. Reversal of rocuronium-induced
neuromuscular blockade with sugammadex in pediatric and adult surgical
patients. Anesthesiology. 2009;110(2):284-94.
20. Liu G, Wang R, Yan Y, et al. The efficacy and safety of sugammadex for reversing
postoperative residual neuromuscular blockade in pediatric patients: A
systematic review. Sci Rep. 2017;7(1):5724.
21. Teixeira J, Matias B, Ferreira I, et al. Sugammadex is changing the paradigm in
neuromuscular blockade in patients with myotonic dystrophy. J Perioper Pract.
2019:1750458919838412.
22. Ahmed S, Naguib A, Tumin D, et al. Use of sugammadex in a patient with
myotonic dystrophy. Cardiol Res. 2018;9(1):50-2.
23. Pickard A, Lobo C, Stoddart PA. The effect of rocuronium and sugammadex on
neuromuscular blockade in a child with congenital myotonic dystrophy type 1.
Paediatr Anaesth. 2013;23(9):871-3.
24. Takeda A, Kawamura M, Hamaya I, et al. Case of anesthesia for thoracoscopic
thymectomy in a pediatric patient with myasthenia gravis: reversal of
rocuronium-induced neuromuscular blockade with sugammadex. Masui.

2012;61(8):855-8.
25. de Boer HD, van Esmond J, Booij LH, et al. Reversal of rocuronium-induced
profound neuromuscular block by sugammadex in Duchenne muscular
dystrophy. Paediatr Anaesth. 2009;19(12):1226-8.
26. Woloszczuk-Gebicka B, Zawadzka-Glos L, Lenarczyk J, et al. Two cases of
the “cannot ventilate, cannot intubate” scenario in children in view of recent
recommendations. Anaesthesiol Intensive Ther. 2014;46(2):88-91.
27. McDonagh DL, Benedict PE, Kovac AL, et al. Efficacy, safety, and pharma
cokinetics of sugammadex for the reversal of rocuronium-induced neuro
muscular blockade in elderly patients. Anesthesiology. 2011;114(2):318-29.
28. Yazar E, Yilmaz C, Bilgin H, et al. A comparision of the effect of sugammadex
on the recovery period and postoperative residual block in young elderly and
middle-aged elderly patients. Balkan Med J. 2016;33(2):181-7.
29. Muramatsu T, Isono S, Ishikawa T, et al. Differences of Recovery from
Rocuronium-induced deep paralysis in response to small doses of sugammadex
between elderly and nonelderly patients. Anesthesiology. 2018;129(5):901-11.
30. Suzuki T, Kitajima O, Ueda K, et al. Reversibility of rocuronium-induced
profound neuromuscular block with sugammadex in younger and older
patients. Br J Anaesth. 2011;106(6):823-6.
31. Dong SW, Mertes PM, Petitpain N, et al. Hypersensitivity reactions during
anesthesia. Results from the ninth French survey (2005-2007). Minerva
Anestesiol. 2012;78(8):868-78.
32. Tsur A, Kalansky A. Hypersensitivity associated with sugammadex adminis
tration: a systematic review. Anaesthesia. 2014;69(11):1251-7.
33. Godai K, Hasegawa-Moriyama M, Kuniyoshi T, et al. Three cases of suspected
sugammadex-induced hypersensitivity reactions. Br J Anaesth. 2012;109(2):
216-8.
34. de Kam PJ, Nolte H, Good S, et al. Sugammadex hypersensitivity and underlying
mechanisms: a randomised study of healthy non-anaesthetised volunteers. Br
J Anaesth. 2018;121(4):758-67.
35. Spoerl D, D’Incau S, Roux-Lombard P, et al. Non-IgE-dependent hypersensitivity
to rocuronium reversed by sugammadex: Report of three cases and hypothesis
on the underlying mechanism. Int Arch Allergy Immunol. 2016;169(4):256-62.
36. Kawano T, Tamura T, Hamaguchi M, et al. Successful management of
rocuronium-induced anaphylactic reactions with sugammadex: a case report.
J Clin Anesth. 2012;24(1):62-4.
37. McDonnell NJ, Pavy TJ, Green LK, et al. Sugammadex in the management of
rocuronium-induced anaphylaxis. Br J Anaesth. 2011;106(2):199-201.
38. Kim GH, Choi WS, Kim JE, et al. Anaphylactic shock after sugammadex
administration, induced by formation of a sugammadex-rocuronium complex.
Korean J Anesthesiol. 2018.
39. Yamaoka M, Deguchi M, Ninomiya K, et al. A suspected case of rocuronium-
sugammadex complex-induced anaphylactic shock after cesarean section.
J Anesth. 2017;31(1):148-51.
40. Ho G, Clarke RC, Sadleir PH, et al. The first case report of anaphylaxis caused
by the inclusion complex of rocuronium and sugammadex. A A Case Rep.
2016;7(9):190-2.
41. De Kam PJ, Grobara P, Prohn M, et al. Effects of sugammadex on activated
partial thromboplastin time and prothrombin time in healthy subjects. Int J
Clin Pharmacol Ther. 2014;52(3):227-36.
42. Raft J, Guerci P, Harter V, et al. Biological evaluation of the effect of sugammadex
on hemostasis and bleeding. Korean J Anesthesiol. 2015;68(1):17-21.
43. Lee IO, Kim YS, Chang HW, et al. In vitro investigation of the effects of
exogenous sugammadex on coagulation in orthopedic surgical patients. BMC
Anesthesiol. 2018;18(1):56.
44. Peeters P, Passier P, Smeets J, et al. Sugammadex is cleared rapidly and primarily
unchanged via renal excretion. Biopharm Drug Dispos. 2011;32(3):159-67.
45. Staals LM, Snoeck MM, Driessen JJ, et al. Reduced clearance of rocuronium
and sugammadex in patients with severe to end-stage renal failure: a
pharmacokinetic study. Br J Anaesth. 2010;104(1):31-9.
46. Panhuizen IF, Gold SJ, Buerkle C, et al. Efficacy, safety and pharmacokinetics
of sugammadex 4 mg/kg–1 for reversal of deep neuromuscular blockade in
patients with severe renal impairment. Br J Anaesth. 2015;114(5):777-84.
47. de Souza CM, Tardelli MA, Tedesco H, et al. Efficacy and safety of sugammadex
in the reversal of deep neuromuscular blockade induced by rocuronium in
patients with end-stage renal disease: A comparative prospective clinical trial.
Eur J Anaesthesiol. 2015;32(10):681-6.
48. Naguib M, Brull SJ. Sugammadex: a novel selective relaxant binding agent.
Expert Rev Clin Pharmacol. 2009;2(1):37-53.
49. Staals LM, de Boer HD, van Egmond J, et al. Reversal of rocuronium-induced
neuromuscular block by sugammadex is independent of renal perfusion in
anesthetized cats. J Anesth. 2011;25(2):241-6.
50. Ma D, Zavalij PY, Isaacs L. Acyclic cucurbit[n]uril congeners are high affinity
hosts. J Org Chem. 2010;75(14):4786-95.
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containers bind neuromuscular blocking agents in vitro and reverse
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52. Hoffmann U, Grosse-Sundrup M, Eikermann-Haerter K, et al. Calabadion: A new
agent to reverse the effects of benzylisoquinoline and steroidal neuromuscular-
blocking agents. Anesthesiology. 2013;119(2):317-25.
53. Haerter F, Simons JC, Foerster U, et al. Comparative effectiveness of calabadion
and sugammadex to reverse non-depolarizing neuromuscular-blocking agents.
Anesthesiology. 2015;123(6):1337-49.
54. Savarese JJ, McGilvra JD, Sunaga H, et al. Rapid chemical antagonism of
neuromuscular blockade by L-cysteine adduction to and inactivation of the
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(AV430A), CW 002, and CW 011. Anesthesiology. 2010;113(1):58-73.
55. Sunaga H, Malhotra JK, Yoon E, et al. Cysteine reversal of the novel neuromuscular
blocking drug CW002 in dogs: pharmacodynamics, acute cardiovascular effects,
and preliminary toxicology. Anesthesiology. 2010;112(4):900-9.
56. de Boer HD, Driessen JJ, Marcus MA, et al. Reversal of rocuronium-induced (1.2
mg/kg) profound neuromuscular block by sugammadex: a multicenter, dose-
finding and safety study. Anesthesiology. 2007;107(2):239-44.
CHAPTER
5 Issues and Management of

Obese Parturient
Swarup Sri Varaday, Preet Mohinder Singh
INTRODUCTION
Obesity is defined as abnormal and excessive accumulation of fat in the body
that has adverse effect on health. Obesity in pregnancy is associated with
increased risk of complications during labor and higher rate of instrumental
delivery and cesarean section.1 It is associated with higher morbidity and
poses a significant challenge to an obstetric anesthesiologist (Fig. 1). This
chapter aims to elaborate on the anesthetic implications of obesity in
relation to labor analgesia and cesarean delivery.
The adverse effects of obesity in pregnancy extend beyond the mother.
Several studies have demonstrated the impact of obesity during antenatal
and intrapartum period, showing higher incidence of morbidity and
mortality during this period affecting the newborn as well. Some of these
systematically reviewed studies provided a set of recommendations for
management of obesity in pregnancy.2 The problem of obesity is unique
Fig. 1: Morbidly obese parturient.

Issues and Management of Obese Parturient 69
given the maternal situation, who is bound to further gain weight resulting
from pregnancy itself.
DEFINING OBESITY IN PREGNANCY—THE DILEMMA!

Body mass index (BMI) is a measure used to classify overweight and obesity.
BMI (kg/m2) is defined as weight in kilograms divided by the square of height
in meters. According to World Health Organization (WHO) population-
based studies, the upper limit of normal BMI in adults is 24.9 kg/m2, and
obesity is labeled once the BMI > 30 kg/m2, anything falling between these
cut-offs is designated as overweight. We would like to mention that a
generalized fit model for all may not be appropriate in pregnancy. By the
end of third trimester, the parturient has nearly 10 kg added to her original
weight (would be even more for multiple gestations). So, it would not be
uncommon to find a normal weight female to be labeled overweight or
obese category just because of the weight gain during pregnancy. Women
within the normal BMI range tend to gain 11.5–16 kg on average during
pregnancy. Many women in the US in their childbearing age have BMI in
the obese range and there is no adequate evidence to develop detailed
guidelines for weight gain in pregnancy. In 2009, the institute of medicine
in the US has recommended a weight gain of 11–20 lbs (4.95–9.0 kg) for
women who are obese and 15–25 lbs (6.8–11.25 kg) for women who are
overweight. We therefore recommend interpretation of these numbers/
classifications with caution when it is applied to pregnant females.
Obesity in pregnancy with high BMI score is associated with several
comorbidities such as gestational diabetes, pre-eclampsia, cardiovascular
and pulmonary disease, postpartum hemorrhage, surgical site infection,
and sepsis.3-5
EPIDEMIOLOGY—THE CHANGE IN LIFESTYLE

Obesity as such has increased in prevalence worldwide in the last 30 years
at an alarming rate. In a survey conducted between 1980 and 2013 showed
28% increase in obesity among adults during that period.6 WHO data from
2014 showed that just less than 2 billion adults in the age group of 18 years
and above are overweight. Pregnant women are no different, in terms of
these epidemiological trends. Recent worldwide survey estimates show
that more than 20% of women in their reproductive age have BMI of 30 or
more.7 More than half of pregnant women in the United States of America
(USA) fall into overweight or obese category (2014 survey). Other than food
habits, there seems to be a strong genetic predisposition toward obesity that
plays a significant role. Obesity is relatively less in Asian countries when
compared to the western countries and is around 10%,7 though trending
upward. According to the recent European survey, data showed that 30–37%
of women in their preconceptual period had BMI in the overweight or obese
category.8
Even though recent maternal mortality rate is trending down worldwide,
astonishingly this rate is on a rise in the USA. In comparison to other
high socioeconomically developed countries America has the highest rate
of maternal mortality and is suspected probably due to high incidence
of obesity in pregnancy.9,10 This increasing trend of obesity in obstetric
population is of concern due to its impact on increased comorbidities.
PATHOPHYSIOLOGY OF OBESITY IN PREGNANCY

The adipocyte (fat cell in adipose tissue) has both storage and endocrine
function. It stores fat and is also known to release hormones such as leptin,
blood pressure regulating hormone angiotensin, and cytokines such as tumor
necrotizing factor (TNF alpha) and interleukin (IL-6). The proinflammatory
mediators are secreted mainly by visceral fat whereas adenopectin and
leptin are produced by subcutaneous adipocytes.11 Increased visceral
adipose tissue in obesity alters neurohormonal signals promoting insulin
resistance, inflammation, and macrophage mobilization into the adipose
tissue further worsening the inflammation. Adipocyte and inflammatory
cell mix is the potent combination at the core of metabolic disturbance in
obesity.12 This problem is further compounded in pregnancy. The hormonal
alterations in pregnancy probably enhance the insulin resistance that may
be pre-existing in obesity. Insulin resistance and inflammation together
with vascular dysfunction contribute in developing complications such as
diabetes mellitus, pre-eclampsia and cardiovascular disease in pregnancy.
OBESE PARTURIENT AND ANESTHESIOLOGIST

What to Anticipate?
The combination effects of physiological changes of pregnancy and obesity
have implications in the anesthetic plan and management of obese
parturient. Pregnancy and anesthesia risks are compounded in obese
population.
Early Anesthesia Consultation

The Royal College of Obstetricians and Gynaecologists (RCOG)13 and
American College of Obstetricians and Gynecologists (ACOG)14 published
guidelines recommending a multidisciplinary team involvement in managing
obese parturient. The recommended guidelines start from preconception
counseling, BMI assessment and screening all pregnant women for obesity,
to monitor BMI periodically and providing guidelines regarding prenatal

weight gain, and to consult with obstetric anesthesiologist in the last
trimester especially pregnant women with high BMI >40. At the time of
this consultation, it is important to perform a detailed history taking and
thorough physical examination identifying possible risk factors for adverse
outcomes. During physical examination, it is important to emphasize on
airway evaluation, respiratory, and cardiovascular systems assessment.
It is important to openly discuss with the patient regarding advantages,
disadvantages, and challenges of performing neuraxial analgesia/anesthesia
for labor verses general anesthesia for cesarean delivery especially focusing
on obesity-related problems. It is also important to mention to the patient
about the possible difficulty in placing spinal or epidural and may take more
time than usual. Patients are encouraged to request for epidural placement
in the early phase of labor, as this would ease out on patient positioning.
Early anesthesiology consultation in pregnancy also allows time to perform
certain investigations and treatment to optimize both the mother and fetus.
Airway
The incidence of failed endotracheal intubation is higher in pregnant
women (1:280) when compared to general population (1:2,500). Obesity in
pregnancy further increases the difficulty to intubate (1:3) or maintain airway
with bag mask ventilation. In a retrospective study, over a 3-year period,
Samsoon and Young found the incidence of failed intubation to be 7 out
of 1,980 anesthetics, in the obstetric population versus the failed intubation
in the general surgical population, which were 6 out of 13,380 patients.15
Unfortunately, specific figures are not available for obese parturient but
one can conclude with a fair bit of confidence that these numbers should
be higher for morbidly obese parturient. It is interesting to note that all
the above figures are generated from a prevideo laryngoscopy era. In all
above cited studies, failed intubation was with direct laryngoscopy. The
incidence of difficult intubation would be less, if it was performed with
video-assisted laryngoscopy.
The risk of failed/difficult intubation and airway complications increase
even more in obese parturient.16,17 The Mallampati score changes due to
increased pharyngeal edema and fatty infiltration of pharyngeal tissue. It is
prudent to thoroughly assess the airway in obese patients and plan ahead
for any emergent or elective operative delivery under general anesthesia.
OBSTRUCTIVE SLEEP APNEA

There are not many epidemiological studies on obstructive sleep apnea
(OSA) in pregnancy. Recent studies estimate that 10–30% women have OSA
during their pregnancy.18-20 OSA is associated with hypertension, diabetes
Table 1: Stop bang questionnaire for detecting obstructive sleep apnea (OSA).
Analyzed variable Questions to be asked/examination findings
S—Snoring Do you snore loudly? Louder than talking or loud enough
to be heard through a closed door.
T—Tiredness Do you often feel tired? Do you sleep during daytime?
O—Observed apnea Has anyone observed you stop breathing during sleep?
P—Pressure Do you have high blood pressure?
B—BMI BMI > 35 kg/m2
A—Age Over 50 years
N—Neck Circumference over 40 cm
G—Gender Male
High risk for OSA: ≥ 3 positive responses
Low risk for OSA: ≤ 3 positive responses
mellitus, cardiomyopathy, and in-hospital mortality.4,21,22 STOPBANG

questionnaire (Table 1) is the general screening tool for detecting OSA but
is suboptimal in pregnancy. OSA in pregnancy is more a dynamic process
and OSA predictors vary in each trimester and their value is improved with
gestational age. Polysomnography still remains the gold standard test for
OSA in pregnancy.
A recent survey in the USA found that majority of the anesthesiologists
were not aware of the risks of OSA and there was no antenatal screening
for this condition. We recommend having a low threshold for evaluating
possibility of OSA in pregnancy. If this is done in early pregnancy, corrective
remedies not only are likely to improve maternal but also fetal outcomes as
well. Pregnant females with OSA are likely to have lower oxygen saturations
and thus fetal oxygen supply may not be ideal. Screening these patients
early in pregnancy and eventual use of continuous positive airway pressure
(CPAP) devices elevates the baseline oxygen saturation in these patients. It
is not surprising to see higher incidence of intrauterine growth restriction
(IUGR) in obese parturients, which may be directly linked to OSA.
Maternal and Fetal Considerations

Obese parturients are at increased risk of developing complications such as
gestational diabetes, pregnancy-induced hypertension, OSA, pre-eclampsia,
fetal macrosomia, birth trauma, prolonged labor, shoulder dystocia,
instrumental delivery, and increased incidence of emergent cesarean
section (Flowchart 1). Chu et al. in their meta-analysis reported increased
incidence of gestational diabetes in obese parturients when compared to
nonobese parturients.23 O’Brien et al. in their systematic review of 13 cohort
Flowchart 1: Risks and complications associated with obesity in pregnancy.
studies demonstrated that increase in preconception BMI leads to increased

risk of pre-eclampsia.24
Obesity is also associated with higher incidence of complications such
as postpartum hemorrhage, thromboembolism, endometritis, and wound
infection. Thromboembolism in pregnancy is a leading cause of maternal
morbidity and mortality in the developed countries. Obesity in pregnancy
further increases this risk. Obese parturient is at increased risk of deep vein
thrombosis (DVT) because of chronic inflammation, hypercoagulable state
in pregnancy, oxidative stress, and venous stasis.25
According to Center for Disease Control (CDC), birth by cesarean section
is 31.9% of all births in America.26 In a large study Kominiark et al. reviewed
124,389 laboring patients, recorded their BMI and route of delivery, and
assessed the impact of BMI on cesarean delivery in these patients. Their
study showed that obese nulliparous women with BMI greater than 40 had
higher cesarean section rate of nearly 42%.27
The success rate of trial of labor after cesarean delivery (TOLAC)
is inversely related to obesity. Some studies suggest leptin, a hormone
predominantly made by adipose cells has inhibitory effect on the uterine
myometrial contraction. Obesity in pregnancy is known to increase the
incidence of preterm delivery.28-30 Maternal obesity is associated with
fetal anomalies such as macrosomia (fetal weight >4,000 g), congenital
malformations and shoulder dystocia.31-34
Respiratory System
In obese parturient, the respiratory system changes (Table 2) of pregnancy
and obesity together have combined effect on the pulmonary mechanics.35 In
pregnancy, functional residual capacity (FRC) is decreased due to cephalad
displacement of the diaphragm by the gravid uterus. Obesity further impairs
respiratory function by decreasing FRC, small airway collapse, basal
Table 2: Respiratory system changes in normal pregnancy, obesity, and in

combination of both.
Parameter Pregnancy Obesity Combined
Progesterone level ↑ ↔ ↑
Sensitivity to CO2 ↑ ↓ ↑
Tidal volume ↑ ↓ ↑
Respiratory rate ↑ ↑↔ ↑
Minute volume ↑ ↓↔ ↑
Inspiratory capacity r ↓ ↑
Inspiratory reserve ↑ ↓ ↑
volume
Expiratory reserve ↓ ↓↓ ↓
volume
Residual volume ↓ ↓↔ ↓
Functional residual ↓↓ ↓↓↓ ↓↓
capacity
Vital capacity (VC) ↔ ↓ ↓
FEV1 ↔ ↓↔ ↔
FEV1/VC ↔ ↔ ↔
Total lung capacity ↓ ↓↓ ↓
Compliance ↔ ↓↓ ↓
Work of breathing ↑ ↑↑ ↑
Resistance ↓ ↑ ↓
V/Q ↑ ↑ ↑↑
PaO2 ↓ ↓↓ ↓
PaCO2 ↓ ↑ ↓
↑ = Increase
↓ = Decrease
↔ = No change
(FEV1: forced expiratory volume in 1 second; PaO2: partial pressure of oxygen;
PaCO2: partial pressure of carbon dioxide; V/Q: ratio of ventilation/perfusion)
Source: SAGE publications (with permission).
atelectasis, shunting in the dependent areas of the lungs, and increased

ventilation-perfusion mismatch. At the same time, obesity increases resting
metabolic rate, work of breathing, and increased oxygen demand. This
combination results in rapid desaturation when lying in supine position or
at the time of induction during cesarean delivery. Adequate preoxygenation
with slightly head up position is vital at the time of induction of anesthesia.
Obstructive sleep apnea is often associated with obesity in pregnancy.
OSA worsens with gestation due increased upper airway congestion and
hyperemia of normal pregnancy or pre-eclampsia. Thus, one should

anticipate difficulty in mask ventilation in these patients. A previous history
of easy airway does not rule out possibility of difficult airway or mask
ventilation when it comes to pregnancy. This combination is deadly for an
obese parturient in view of loss of reserves to compensate.
Cardiovascular changes normally seen in pregnancy are increase in blood
volume by 50%, heart rate 20%, stroke volume by 30%, and cardiac output
reaching 140% over the gestational period. Obese parturient may poorly
tolerate these changes due to associated risk factors like systemic and
pulmonary hypertension, ischemic heart disease, and congestive heart
failure.
Obese patients tend to have diastolic cardiac dysfunction. In a nonobese
parturient, increase in blood volumes may be well tolerated. However,
diastolic dysfunction in an obese parturient can tipple this fine balance to
a clinically relevant heart failure. The lung changes discussed above can lead
to lower PaO2 and thus chances of previous ischemic cardiac conditions
becoming more detrimental in an obese parturient. An exacerbated supine
hypotension response is observed in obese parturient due to aortocaval
compression from gravid uterus and presence of excessive intra-abdominal
fatty tissue.
Gastrointestinal System
Obese pregnant mothers are more at risk for aspiration than nonobese
parturients. In pregnancy progesterone relaxes smooth muscle, reduces
lower esophageal sphincter tone, and increases gastric acidity by increasing
the production of placental gastrin. Studies have shown that pregnancy as
sole factor does not slow down gastric emptying36,37 but labor pain and
opioids used for labor analgesia may delay gastric emptying. All women
in labor are inevitably at risk of aspiration. Gastric emptying is further
decreased in obese parturient with increased abdominal pressure due
to large abdominal panniculus, presence of hiatal hernia, and diabetes
mellitus. Fasting guidelines similar to nonobstetric patient for general
anesthetic is applicable to all parturients whether obese or nonobese
if proceeding with surgical intervention. Preoperative acid aspiration
prophylaxis, rapid sequence induction and intubation with cricoid pressure
are strictly indicated for all obese paturients undergoing general anesthesia
for operative delivery.
LABOR ANALGESIA
According to ACOG and American Society of Anesthesiologists (ASA),
maternal request is sufficient indication for pain relief during labor, barring
medical contraindications. Studies have shown that the duration of labor in
obese women with high BMI is prolonged than in nonobese parturients.38
Melzack et al. reported labor contractions can be more painful in obese
parturients due to fetal macrosomia, cephalopelvic disproportion, and labor
induction showing a positive correlation between BMI and labor pain.39
However, these findings were questioned in a study by Ranta et al.40
Parenteral opioids such as meperidine (pethidine), fentanyl, and
inhalational agents like Entonox (50% nitrous oxide in oxygen) are to be
used with caution in the obese due to increased risk of sedation, respiratory
depression, nausea, and vomiting. Neuraxial block remains the most preferred
method of labor analgesia. This includes epidural, combined spinal epidural
(CSE), dural puncture epidural (DPE), and continuous spinal analgesia.
DPE is a modified version of CSE where the duramater is intentionally
perforated by the spinal needle introduced through the epidural needle but
no intrathecal medication is administered. This technique is known to have
local anesthetic spread caudally and produce better block when compared
to standard continuous epidural technique.41 Neuraxial analgesia provides
excellent pain relief in labor. Maternal and fetal complications and risks
associated neuraxial blocks are minimal, though the procedure is associated
with technical challenges in obese parturient. Edward et al. in their study on
lumbar punctures in neurology clinics noted that BMI as single factor has
inverse correlation to success.42 Use of ultrasound imaging may overcome
this problem. A good functional epidural not only helps in relieving pain
during labor but also can be utilized in the event of emergent cesarean
delivery in order to avoid the risks of general anesthesia.
Epidural for Labor

Epidural placement can be challenging in the morbidly obese parturients
due to obscured surface landmarks, requiring multiple attempts. Truncal
obesity with thick subcutaneous fat causes misidentification of midline,
increased depth of epidural space needing longer needles, misplacement
of epidural catheter, and higher rate of accidental dural puncture. In obesity,
the surface landmarks of the spine are better appreciated in sitting position
than in lateral decubitus position. Excess subcutaneous fatty tissue can
create false pockets and false loss of resistance during epidural placement.
Preprocedural ultrasonography for epidural placement has become a
popular bedside tool for identifying the midline, approximate depth of the
epidural space, the point of insertion, and trajectory of the needle. Use of
ultrasound has shown to reduce number of attempts in finding epidural

space and lowered accidental dural puncture and epidural failure rates.43,44
However, in the presence of increased subcutaneous fatty tissue in the
morbidly obese with depth of epidural space >10 cm makes ultrasound
visualization more challenging and less predictable. In morbidly obese
patient, the skin surface marking after identifying the epidural space for
insertion of needle moves 1 or 2 more spaces when patient arches her
back because of the loose skin sliding over the fatty subcutaneous adipose
tissue. Increased movement of surface marking makes epidural placement
very challenging even with use of ultrasound. Another important factor for
failed epidural and inadequate analgesia in obese parturient is migration
of epidural catheter due to excess movement of skin and subcutaneous
tissue.45 Securing the epidural catheter firmly with adhesive tape at the point
of insertion will reduce dislodgement.
ANESTHESIA FOR CESAREAN SECTION

Neuraxial anesthesia still remains the preferred choice over general
anesthesia for cesarean section unless there is a contraindication.
Equipment
Many labor units are often caught unprepared when it comes to meeting
the special needs of morbidly obese parturients. Sphygmomanometers with
extra-large blood pressure cuffs are essential for measuring blood pressure
in morbidly obese. If still not able to record blood pressure, invasive blood
recording is advised for surgery by placing an arterial line. The weight and
size of operating room tables must be sufficient to accommodate morbidly
obese patients. The newer bariatric OR tables can accommodate weight
capacities up to 1,000 pounds.
Spinal Anesthesia
Single-shot spinal anesthesia with instillation of local anesthetic and opioid
is a common technique for cesarean section. It provides a dense and
reliable sensory motor block. Advantage of this block is quick onset, lower
incidence of postdural puncture headache especially if smaller size pencil
point needles (25 g, 27G Whitacre or Sprotte needles) are used. The biggest
disadvantage of spinal anesthesia is that its duration of action is limited.
Spinal block may not be ideal in a morbidly obese parturient because the
total operative time for cesarean section can be more than 2 hours. The
incidence of high spinal block rate is seen in morbidly obese parturient
due increased intra-abdominal pressure from the panniculus and less
cerebrospinal fluid (CSF) in the spinal space due to epidural fat.46,47 Use of
spinal catheters may overcome these problems by providing slow titrating

doses till desired sensory level is reached and maintained for the duration of
surgery. Disadvantage with spinal catheters is postdural puncture headache,
though less common in morbidly obese parturient.48
Epidural Anesthesia
Epidural placement in morbidly obese can be technically more challenging.
Usually encounter false loss of resistance due to thick subcutaneous
adipose tissue is leading catheter misplacement and increased resistance
is encountered in threading the catheter into the epidural space. Sacral
sparing of sensory block is encountered with epidural blocks and may need
some systemic analgesic supplementation. A good functioning epidural
used for labor can be dosed with higher concentration local anesthetic for
cesarean delivery.
The advantage of epidural over spinal is that it can be used for the whole
duration of surgery and for postoperative pain management if needed. High
sensory motor block can occur with standard local anesthetic doses used
due to decreased epidural space in morbidly parturient. It is prudent to
use smaller volume of local anesthetic and administer intermittent doses
to achieve desired level of anesthesia.
Combined Spinal Epidural

Combined spinal epidural is a popular neuraxial technique for C-section
in obese parturients. It has the advantage of providing quick and dense
block from spinal component and has the benefit of epidural catheter in
providing supplemental doses of local anesthetic, prolonging the anesthetic
for the duration of cesarean section. Studies have shown CSE increases the
success rate of epidural catheter placement in the correct anatomical space
if CSF is visually confirmed in the spinal needle hub.49 To avoid causing high
spinal block and profound hypotension in the morbidly obese, a low dose
spinal with epidural (CSE) is recommended. In this technique, smaller dose
of spinal and slow titrated doses of epidural local anesthetic are used to
achieve adequate sensory level for operative delivery. Though CSE appears
to take longer duration of time due to multiple steps involved, Ross et al. in
their study demonstrated that there is no significant difference in the time
taken for spinal block versus CSE.50
General Anesthesia
The risk of aspiration is a big concern in every parturient for surgical
intervention more so in obese parturient. Wong et al. in their recent
study did not observe any difference in gastric emptying in obese versus
nonobese nonlaboring parturients.36 Preoperative fasting guidelines for

obese parturient are similar to general population scheduled for surgery.
Point of care ultrasound for visualization of gastric contents is becoming
more popular tool recently.
Respiratory system changes in obese parturient have a great impact
in pulmonary mechanics. Rapid oxygen desaturation in supine position
occurs in obese due reduced chest compliance, cephalad displacement
of diaphragm, reduced lung volume, and FRC with the combination of
increased oxygen consumption resulting in rapid oxygen desaturation at the
time of induction of anesthesia. Desaturation can be minimized by adequate
preoxygenation with 100% oxygen for at least 3 minutes before induction
or at minimum 3 large deep breaths (vital capacity) for emergent operative
delivery. Ramped, head up position, or reversed Trendelenburg position is
known to change respiratory mechanics and improve oxygenation in the
obese parturient.
Obesity is considered as an independent risk factor for difficult airway
in pregnancy.51 Patients with large neck circumference, fat pad between
the shoulders, and high Mallampati score are known to cause difficult
laryngoscopy and intubation. The important component of laryngoscopy
and intubation is proper positioning of the patient. Head up and ramped
position with supporting blankets or commercially available foam ramp
improves the intubating conditions by allowing alignment of oropharynx
with larynx when compared to standard “sniff” position.52 The use of video
laryngoscope in obese improves the laryngeal and Cormack and Lehane
view of the glottis, reduces the number of failed attempts, incidence of
desaturation (drop in SpO2), and airway trauma.53 If difficult airway is
predicted in a morbidly obese parturient, fiberoptic bronchoscope should
be readily available in the operating room for awake fiberoptic intubation.
Distribution and dose response to anesthetics drugs are altered in obesity.
Dosing of intravenous anesthetic agents and depolarizing muscle relaxants
are calculated according to total body weight whereas nondepolarizing
muscle relaxants dosage is based on ideal body weight.54 Prolonged sedation
from anesthetics and opioid analgesics should be expected in obese
patients. Desflurane is associated with faster recovery than sevoflurane in
morbidly obese patients. It is recommended to insert orogastric tube and
empty the stomach before emergence to avoid aspiration risk. Extubation is
done in propped up position after confirming that the patient is adequately
reversed, fully awake, and spontaneously breathing.
POSTOPERATIVE MANAGEMENT
Obese parturients have higher incidence of complications such as airway
obstruction, respiratory depression, CO2 retention, somnolence, atelectasis,
and hypoxia in the immediate postoperative period. Respiratory support

such high flow oxygen mask, nasopharyngeal airway (may cause bleeding),
and non-invasive positive pressure ventilation [CPAP and biphasic positive
airway pressure (BIPAP)] may be required in obese parturient with OSA. It is
recommended to monitor these patients using telemetry in the labor ward or
admission to high dependency observation unit depending on the severity
of comorbidities. The medical and nursing staff in labor ward should be clear
regarding instructions for monitoring and how anesthesiology providers
can be contacted for advice. Multimodal analgesics with nonsteroidal anti-
inflammatory drugs and regional nerve blocks, e.g. transverse abdominis
plane block, are preferred over opioids. Deep breathing exercises
and incentive spirometry may prevent lung atelectasis and hypostatic
pneumonia.
Decreased mobility in obesity in combination with hypercoagulable
state of pregnancy is associated with increased risk of developing DVT
and pulmonary thromboembolism.55 It is strongly recommended to
use pneumatic compression stockings and prophylactic anticoagulants
(subcutaneous unfractionated or low molecular weight heparin) and early
ambulation should be encouraged. The anticoagulant doses should be
based on actual body weight to have optimal effect.
CONCLUSION
Obesity has become more prevalent in pregnant population worldwide.
Obesity in pregnancy is associated with increased morbidity and mortality
and requires multidisciplinary management involving experienced
anesthesiologists, obstetricians, neonatologists, and nursing staff. Early
consultation with an obstetric anesthesiologist is recommended to evaluate
for comorbidities and provide best peripartum care. It is encouraged
to provide early epidural analgesia in labor and to periodically ensure
that it is functional. Existing labor epidural can be utilized for neuraxial
anesthesia if proceeding with cesarean delivery and may avoid the
complications of general anesthesia. Providing adequate postoperative
pain relief and thromboprophylaxis is very essential in this population.
Careful postoperative monitoring with telemetry or high dependency unit
admission is recommended.
KEY POINTS
• Obesity in pregnancy is associated with several comorbidities and may
lead to complications both in the mother and baby.
• Experienced anesthesiologists as a part of multidisciplinary team
should manage morbidly obese parturients. A comprehensive prenatal
anesthesiology consultation is recommended.
• Neuraxial anesthesia is recommended choice of labor analgesia and for

cesarean section. Neuraxial procedures may be facilitated by ultrasound
guidance.
• A strategical plan for difficult airway management is essential and must be
discussed in advance. A fully equipped difficult airway cart with fiberoptic
bronchoscope must be readily available.
• Additional specialized equipment may be necessary for logistics–operating
tables that accommodate bariatric patients, large blood pressure cuffs, etc.
• Head up ramp or sitting position may aid at the time of induction and
endotracheal intubation for cesarean delivery. Video-assisted laryngoscopy
is recommended.
• Long acting opioids and sedatives used with caution to avoid respiratory
depression.
• Incidence of wound infection and venous thromboembolism (VTE) is high.
Appropriate dosing of antibiotics and thromboprophylaxis recommended.
(To follow institutional guidelines).
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Postoperative Delirium: A Bane of Daycare Surgery 85
CHAPTER
6 Postoperative Delirium: A Bane

of Daycare Surgery
Deep Arora, Deepak Pahwa
INTRODUCTION
Last few decades have seen rapid advancements in the field of anesthesia
as well as surgery. These advancements have helped in faster postoperative
recovery of patients, leading to increasing popularity of daycare procedures.
James Nicoll, first published his work on daycare surgery in British Medical
Journal in 1909.1 A survey conducted in 2006 showed that almost 80% of
surgeries performed in the United States and Canada are done as daycare
surgeries.2 Bajwa et al. quoting unpublished sources estimating that daycare
surgeries account for around 11–23% of total surgeries performed in hospital
settings in India.3
As the daycare procedures are becoming popular, more and more patients
at the extremes of age are presenting for surgeries. With the gradually
increasing proportion of elderly in our population, daycare surgeries in
this age group present their unique challenges for anesthesiologists. As
per United Nations World Population Ageing report, the number of senior
citizens is expected to grow to 2.1 billion by 2050.4
IMPORTANCE OF POSTOPERATIVE DELIRIUM

Postoperative delirium (POD) in the context of daycare surgery is important
because of its high incidence in postoperative elderly patients and its
association with other complications. Postoperative delirium leads to
increased duration of stay in the hospital, increased morbidity, mortality,
increased cost of care and thus, can be the bane of daycare surgery. About
one-third of POD may be preventable. Dr Julia R Berian and her colleagues
have proposed that POD management should be seen as a target for surgical
quality improvement and counted as a parameter of hospital performance.5
Weinrebe et al. through a retrospective study concluded that additional cost
imposed on the hospital per hyperactive delirium patient was around 1200
euro.6
DEFINITION AND INCIDENCE

As per DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th
edition) criteria, delirium is defined as disturbance of consciousness, with
reduced ability to focus, sustain, or shift attention, change in cognition
that is not better accounted for by a pre-existing, established, or evolving
dementia, and that develops over a short period.7 Delirium that manifests
after the patient has undergone a surgical procedure or anesthesia is called
POD. There is wide variation in incidence of POD. It varies from 9–87% and
depends on patient characteristics and the kind of surgery.8 Postoperative
delirium usually manifests between 1 day and 3 days after surgery. It may be
difficult to differentiate POD from emergence delirium and postanesthesia
care unit (PACU) delirium. Emergence agitation is defined as agitation that
starts once the inhaled anesthetics are discontinued. Emergence delirium is
quite common, occurs in 8–20% of patients while awakening from general
anesthesia and is more common in younger age group.9
Features of delirium that start at least 30 minutes after arrival in PACU
are termed as PACU delirium. If signs of delirium are present on arrival in
PACU, they should be labeled as emergence delirium.9 PACU delirium is
significant as patients who develop PACU delirium are at a higher risk of
developing POD.10
PATHOPHYSIOLOGY OF POSTOPERATIVE DELIRIUM

Researchers have proposed a number of theories to explain delirium. The
system integration failure hypothesis (SIFH) has been recently described to
explain the clinical manifestations of delirium. Multiple theories that have
been earlier proposed are brought together and taken into a paradigm in
SIFH. It states that any insult in predisposed individuals results in altered
levels of neurotransmitters and failure of complex brain interconnections,
leading to abnormal and variable response by the brain which manifests
as delirium. The changes in the levels of various neurotransmitters that are
commonly seen in delirium include reduced availability of acetylcholine,
increased levels of dopamine, norepinephrine, glutamine, and altered
levels of gamma-aminobutyric acid (GABA), 5-hydroxytryptamine, and
histamine. Such insults lead to aberrant activation of parasympathetic
system and upregulation of pathological signaling of neurotransmitters.
These signals activate both early as well as late triggers of apoptosis
resulting in manifestations of acute as well as persistent delirium. The SIFH
postulates that humans have various predisposing physiologically fragile
characteristics. These fragile characteristics determine the susceptibility of
individuals to various precipitating factors in an inverse relationship. Thus,
more the fragile characteristics that an individual has, lesser the insult
required to precipitate delirium.11
Helene et al.12 recently proposed the glymphatic theory of delirium.

Glymphatic system is the perivascular transit passageway which helps in
transporting metabolic waste from the brain. It is observed that glymphatic
system transport is increased during sleep associated with slow delta
waves on electroencephalogram (EEG). Any insult that leads to decrease
in glymphatic system mediated transport of waste products from the brain
leads to increased probability of delirium. They hypothesized that patients
given drugs like dexmedetomidine have a lower incidence of delirium as
these drugs improve the glymphatic system mediated drainage of waste
metabolites from the brain.12
RISK FACTORS FOR DEVELOPMENT OF

POSTOPERATIVE DELIRIUM
Patients have various inherent risk factors in the preoperative period
that predispose them for the development of delirium. Similarly, various
precipitating events perioperatively trigger the onset of delirium. The
chances of a patient developing delirium increase exponentially with the
number of predisposing and precipitating factors that one has. These factors
can be present preoperatively, intraoperatively or postoperatively (Table 1).
Table 1: Risk factors for development of postoperative delirium.

Preoperative Intraoperative Postoperative
•• Age •• Duration of surgery •• Pain
•• History of stroke •• Intraoperative blood loss •• Complications
•• Cardiovascular disease •• Site of surgery (abdominal •• Indwelling
•• Peripheral vascular disease and thoracic) catheters
•• Diabetes •• ?Depth of anesthesia
•• Anemia monitoring
•• Parkinson’s disease •• Drugs: Opioids,
•• Depression benzodiazepines,
•• Chronic pain antihistaminics,
•• Anxiety disorders anticholinergics, and TCAs
•• Higher ASA physical status
•• Preoperative fasting and
dehydration
•• Sodium imbalance
•• Drugs with anticholinergic
effects
•• Alcohol-related disorders
•• Emergency surgery
•• Hypothermia on admission
•• Preoperative cognitive
dysfunction
(ASA: American Society of Anesthesiologists; TCAs: tricyclic antidepressants)
Anesthesia and delirium share a complex relationship which is not yet

fully elucidated. A number of drugs have been found to be associated with
delirium. Drugs like benzodiazepines, antihistaminics, anticholinergics,
and tricyclic antidepressants should be avoided especially in vulnerable
patients.13 Use of depth of anesthesia monitoring has been advised by
European Society of Anesthesiology13 but not by the American Geriatric
Society.14 A recent article published in Journal of American Medical
Association (JAMA) also did not find reduced incidence of delirium by using
depth of anesthesia monitoring.15 Hesse et al. found EEG burst suppression
during maintenance of anesthesia and lack of dominance of spindles during
emergence to be strongly linked with PACU delirium.16
There is no advantage of total intravenous anesthesia (TIVA) technique
over inhalational technique for reducing the incidence of POD. A Cochrane
review published in 2018 found no difference in the incidence of POD in
elderly undergoing noncardiac surgery under inhalational anesthesia or
TIVA. But the same review found low quality evidence that maintenance
with propofol-based TIVA reduced the chances of cognitive dysfunction
postoperatively in the elderly.17 Duan et al. in a meta-analysis found that
dexmedetomidine use during or after surgery was associated with reduced
incidence of POD. They suggested that dexmedetomidine should be used
perioperatively to prevent POD. However, they concluded that further
research is needed to determine the appropriate dose and timing of
dexmedetomidine administration.18
Patients undergoing cardiac and vascular surgeries have higher chance
of POD.13 Similarly, patients having any other complication in postoperative
period have higher incidence of POD.13 Wang et al. used STOP-BANG
questionnaire in patients undergoing thoracic surgery and found that
patients with a score at least 3 had higher incidence of obstructive sleep
apnea (OSA), longer duration of POD and coma. These subjects had 3.6
times more likelihood of developing POD and coma as compared to controls
in this study.19
CLINICAL PRESENTATION AND DIAGNOSIS

Any acute or subacute deterioration in behavior or cognition in predisposed
individual should make a clinician to suspect delirium. Delirium can
present as hypoactive form, hyperactive form or mixed form, the incidence
of which is approximately 50%, 25%, and 25% respectively.20,21 Patients with
hyperactive form of delirium usually present with agitation, restlessness,
delusion, and hallucinations. On the other hand, patients with hypoactive
delirium may present with reduced movements, decreased responsiveness
and paucity of speech. Hypoactive delirium is usually misdiagnosed as
depression. Farrell et al. concluded that up to 42% of patients referred to
Flowchart 1: Workup for postoperative delirium.
(CBC: complete blood count)
psychiatry consultation for evaluation and treatment of depression had

delirium.22 Increased mortality rates have been observed in patients with
undiagnosed hypoactive delirium.20
A thorough physical and neurological examination should be performed
in all the patients. Patients presenting with features suggestive of delirium
should be evaluated in detail. Electrolyte derangements, metabolic
disturbances, sepsis or signs of organ dysfunction should be specifically
looked for. Conditions like drug overdose, hepatic or uremic encephalopathy,
substance abuse and withdrawal have targeted treatments and should not
be overlooked while making the diagnosis (Flowchart 1).15
Neuroimaging can be helpful in presence of focal neurological deficits
or deteriorating consciousness. It is advisable to perform lumbar puncture
in patients with suspected meningitis or encephalitis. Early diagnosis of
delirium improves the prognosis of the patient. Delayed diagnosis puts
an additional burden on the finances of the healthcare system. Weinrebe
et al. in a retrospective study found significantly shorter hospital stay (6.85
vs 13.61 days) in patients in whom delirium was detected early.6
DELIRIUM SCREENING
Early diagnosis of delirium is important for faster and effective treatment.
Patients should be shifted out of recovery room only after they are screened
for delirium. For diagnosing delirium as per DSM-5 guidelines, patients
with a severely reduced level of arousal, but above coma (of acute onset)
should be considered as having delirium. (Since hypoactive delirium, the
more common form of POD, is often missed). As patients are sedated in
the recovery room, Richmond Agitation-Sedation Scale (RASS) along with
another delirium screening tool should be used to recognize delirium
in recovery area.13 RASS is a commonly used scale to assess the state of
alertness in ICU patients where a score of +4 is given to a combative patient
on one extreme while an unarousable patient scores –5. Getting a RASS
score is the first step in screening for delirium in a postoperative patient
(Fig. 1).
Fig. 1: Richmond Agitation-Sedation Scale (RASS).
Confusion Assessment Method (CAM) score is the most commonly used

method for screening for delirium. CAM score incorporates four core
features of delirium; acute onset, fluctuating course, inattention, and altered
level of consciousness. It is especially useful in patients with pre-existing
dementia with sensitivity of 94–100% and specificity of 90–95%.23 But, it
requires specific training for its use in the recovery area.
Nursing Delirium Screening Scale (NU-DESC) has the advantage that
it can be easily used in the recovery area and does not require specific
training. NU-DESC is based on 24 hour cycle of observation, so it cannot
be used in daycare settings.24
4As test (4AT) can also be used for screening of delirium. It consists
of two cognitive tests, assessment of level of consciousness, and an acute
change in mental state.24
A two-item questionnaire with “months of years backward” and “what
is the day of the week” can also be used to screen for delirium. It requires
minimal time and training. Fick et al. in a study reported a sensitivity of 93%
and specificity of 64% of two-item questionnaire for detecting delirium.25
Since detection of delirium requires an accurate history, which patients in
delirium may not be able to give, the Family CAM (FAMCAM) questionnaire
has been developed. The source of history in FAMCAM is any informal

caregiver who knows about the patient.26 This questionnaire is especially
important since POD usually develops 1–3 days after surgery and thus can
help in early detection of POD after discharge.
Focused screening also helps in instituting preventive measures at the
earliest thus reducing the complications and the cost of POD.27 American
Geriatrics Society and the Association of Anaesthetists in Great Britain
and Ireland recommend delirium risk assessment of elderly patients prior
to administration of anesthesia.14 It is advisable that the whole team in a
daycare center be involved to decide as to which screening tool is to be
used. The team members should be trained regarding the basic features of
delirium and the screening method that is going to be used.
DIFFERENTIAL DIAGNOSES
Common conditions which need to be differentiated from delirium include
dementia, depression and psychosis.28 Knowledge of patients’ baseline mental
status is essential to make a diagnosis. One should look for acute variations
in patient’s mental status: in delirium these changes occur over hours to
days. A reliable informant is a must while obtaining history.
Dementia often coexists with delirium and is a major predisposing
factor for development of delirium. Acute alteration in patient’s cognition
and consciousness goes more in favor of delirium. Inattention is more
common in delirium while it occurs quite late in dementia.28 It is important
to recognize the subset of patients who have delirium superimposed on pre-
existing dementia. This group of patients have earlier decline of cognition,
frequent and prolonged hospitalizations, and increased mortality.15
Patients with hypoactive delirium can often present with features of
depression. Patients with depression may have altered level of cognition but
their level of consciousness is usually normal in contrast to patients with
delirium.28
Patients with psychotic illnesses like schizophrenia also need to be
differentiated from delirium. Patients with delirium often have acute or
subacute presentation, they usually do not have any history of psychiatric
illness, and they frequently have visual hallucinations, impaired memory and
clouding of consciousness. These features are not present in schizophrenia.28
PREDICTION OF POSTOPERATIVE DELIRIUM

Researchers have tried to formulate various nomograms to predict the
chances of patients developing delirium. Delirium Elderly At-Risk (DEAR)
instrument was proposed by Freter et al. in 2005.29 This instrument
incorporates known risk factors for POD in routine preoperative nursing
assessment. They found it to be useful in identifying elective arthroplasty
Table 2: Delirium Elderly At-Risk (DEAR) instrument.

Domain Yes No
Elderly > 80
Hearing/visual aid
Dependence in activities of daily
living (bathing, dressing, grooming,
toileting, feeding)
Takes >3 times/week
Alcohol
Benzodiazepines
Cognitive impairment
Fig. 2: Predictive nomogram for postoperative delirium devised by Zhang et al.

(ASA: American Society of Anesthesiologists; ICU: intensive care unit; RBC: red blood
cell)
patients at high-risk of developing POD. They used five domains to predict

patients at enhanced risk of developing delirium. Affirmative answers
to more than one domain placed patients into higher risk (for delirium)
category. It is summarized below in the tabular form (Table 2).
Zhang et al. did a retrospective study on 1,156 patients undergoing
fracture neck of femur surgery at their institution. They developed a
nomogram to predict the chances of POD in surgical patients as summarized
in Figure 2.30 This predictive nomogram was constructed based on the
multivariable model. To use the nomogram, a vertical line is drawn up to
the top point row to assign points for each variable. Then, the total number
of points is calculated, and a vertical line is drawn downward from the total
point row to obtain the probability of POD.
BIOMARKERS
Various biomarkers have been proposed to be increased in delirium. These
biomarkers can help in understanding the pathophysiology of POD, refining
the treatment strategies, prognosticating the patients and identifying the
high-risk patients. These include C-reactive protein (CRP), insulin-like
growth factor 1, interleukin-6, apolipoprotein-E genotype, cholinesterases,
GABA, and leptin. A recent review by Ayob et al. concluded that among all
of the above markers, CRP was found to be linked with POD in 5 studies.
They concluded that CRP as a biomarker showed the most potential to be
used for POD but further research is still warranted before any biomarker
gets incorporated in the guidelines for monitoring POD.31 Various studies set
different cutoff values of CRP for identifying delirium but the authors in the
above review concluded that a value of > 3 mg/L can be used reasonably
for predicting POD.31
PREVENTION AND TREATMENT OF

POSTOPERATIVE DELIRIUM
There are many possible ways to prevent or reduce the incidence of POD.
These may be nonpharmacological and pharmacological interventions.
Nonpharmacological interventions should be started preoperatively
(Table 3). They help in reducing the incidence of POD by half.8
Table 3: Nonpharmacological measures for preventing delirium.

Preoperative Intraoperative Postoperative
•• Divide into low-risk and •• Avoid fluctuations in BP •• Decrease pain
high-risk •• Intraoperative depth of •• Avoid
•• Decrease pain anesthesia monitoring benzodiazepines
•• Avoid benzodiazepines •• Avoid benzodiazepines, •• Maintain circadian
•• Maintain circadian rhythm antihistaminics, rhythm
•• Use hearing and visual aids anticholinergics •• Use hearing and
•• Fast-track surgery •• Minimize duration of visual aids
•• Minimize fasting time surgery •• Encourage
•• Minimize blood loss communication
•• Avoid indwelling
catheters
•• Avoid physical
restraints
•• Early mobilization
and nutrition
•• Minimize opioids
BP: blood presssure
Box 1: HELP team interventions.

•• Geriatric nursing assessment and intervention: Screen all patients > 70 years
•• Inclusion: Even if one risk factor
•• Geriatrician consult
•• Interdisciplinary meeting based on risk factors
•• Individualized interventions
•• Adherence: Compliance of all interventions
•• Transitional care: Community linkage and telephone follow-up
(HELP: Hospital Elder Life Program)
The Hospital Elder Life Program (HELP) is a set of multicomponent

interventions that are used to lessen the incidence of delirium in the elderly.
It focuses on interventions aimed at six known risk factors for delirium:
(1) impaired cognition, (2) volume depletion, (3) psychoactive medicines, (4)
visual/hearing impairment, (5) immobilization, and (6) sleep deprivation.32
The members present in a typical HELP team include—Elder Life Specialist,
Elder Life Nurse Specialist, and geriatrician along with trained volunteers.33
HELP team interventions are summarized in Box 1. A recent meta-analysis
on effectiveness of HELP found that this program helped in significantly
reducing the delirium incidence, rate of accidental falls as well as the
duration of stay in the hospital.34
In the preoperative period, patients should be categorized into low-risk
and high-risk categories based on the predisposing and precipitating risk
factors present. Routine use of benzodiazepines as premedication should
be avoided except in those patients who are highly anxious or alcohol
dependent. Similarly, premedication with anticholinergic drugs should be
avoided in all patients. Fasting time should be minimized and surgery fast
tracked to reduce the incidence of delirium. Alpha 2 agonists can be used
in high-risk patients either preoperatively or intraoperatively. Pain should
be adequately assessed and treated perioperatively.13 Intraoperative depth
of monitoring can be used, but whether it helps in reducing the incidence
of delirium is still questionable.
Nonpharmacological measures should be started at the earliest. They
include maintaining orientation by keeping a clock near the patient,
communicating frequently with the patient, encouraging the family
members to interact with the patient, allowing the patient to use his/
her visual/hearing aids for the maximum time possible, reducing the
unnecessary noise in the surroundings and facilitation of sleep by providing
uninterrupted period for sleep during night, discouraging daytime napping,
avoiding physical restraints, avoiding unnecessary indwelling catheters,
mobilizing the patient as soon as possible postoperatively and by allowing
early nutrition. Delirium should be diagnosed at the earliest and treatment
should be started immediately. One should aim to treat the underlying

cause if found.13
Statins have been shown to produce mixed results in preventing delirium.
Bouhout et al. found that “off-pump” coronary artery bypass patients
receiving statins preoperatively had statistically significant reduction in the
incidence of POD.35 Ketamine, in a small randomized controlled trial, in a
dose of 0.5 mg/kg given intravenously only once, was found to decrease
POD and CRP levels.36
Pharmacological treatment should be started as a last resort only if the
patient tries to harm himself or others. For symptomatic treatment, if patient
is admitted in a monitored environment like ICU, a loading dose of 2 mg
haloperidol is administered intravenously. It can be repeated every 15–20
minutes if the agitation persists. If the agitation is severe, double the dose
can be repeated after 15–20 minutes. If the patient is admitted in the ward,
an initial dose of 1–2 mg haloperidol can be given orally, intramuscularly or
intravenously followed by 0.25–0.5 mg every 4 hours.37 In both these settings
haloperidol is tapered over several days.37 Other atypical neuroleptics like
risperidone can be used, but are not found to be superior to haloperidol.38
While treating with neuroleptics one should watch for side effects like
prolonged QT interval and extrapyramidal side effects.
COGNITIVE OUTCOME OF POSTOPERATIVE DELIRIUM

Patients developing delirium have prolonged cognitive adverse effects. Those
who do not develop delirium regain baseline cognitive function 1 month
after surgery, while those who have delirium are not able to do so even
1 year postoperatively.39 Hudetz et al. found that cardiac surgery patients
who develop POD have 14 times higher chances of postoperative cognitive
dysfunction (POCD).40 There is also an increased incidence of dementia in
those who had suffered from delirium. Witlox et al. in a meta-analysis found
that patients with delirium were predisposed to develop dementia (62.5%
vs 8.1%).41
CONCLUSION
Due to advancements in technology, daycare surgeries are gaining
popularity. Daycare surgeries help in improving patient satisfaction, early
mobilization, faster recovery, and decrease health cost for both the patient
and the healthcare system. These facilities help in fast tracking the surgeries,
decreasing the fasting duration, personalized care, and recovery in a familiar
environment, all these factors reduce the incidence of POD. Each and every
patient should be screened for delirium before getting discharged. Daycare
setup also requires facilities to take care of POD, if a patient develops it. Early
recognition and initiation of treatment of POD by trained staff can help in

reducing the incidence as well as severity of delirium. Nonpharmacological
measures if initiated on time can manage most of the cases of POD.
KEY POINTS
• Delirium that manifests after the patient has undergone a surgical
procedure or anesthesia is called POD.
• Postoperative delirium usually manifests between 1 day and 3 days after
surgery.
• The chances of a patient developing delirium increase exponentially with
the number of predisposing and precipitating factors that one has.
• Delirium risk assessment should be done in elderly patients prior to
administering anesthesia.
• Delirium can present as hypoactive form, hyperactive form or mixed form.
• Delirium should be differentiated from dementia, depression, and psychosis.
• Early diagnosis and treatment of POD helps in reducing the morbidity as
well as mortality.
• Nonpharmacological interventions form the mainstay of treatment of POD.
• These interventions should be started in the preoperative period and
should be continued till the patient recovers completely.
• Pharmacological treatment should be reserved as a last resort only if the
patient tries to harm himself or the others.
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and evolution of delirium signs in the post-anaesthesia care unit. Br J Anaesth.
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10. Hernandez BA, Lindroth H, Rowley P, et al. Post-anaesthesia care unit delirium:
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11. Maldonado JR. Delirium pathophysiology: An updated hypothesis of the

etiology of acute brain failure. Int J Geriatr Psychiatry. 2018;33:1428-57.
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Relation to Anesthesia and Sleep States. Anesth Analg. 2019;128(4):747-8.
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14. American Geriatrics Society Expert Panel on Postoperative Delirium in Older
Adults. Postoperative delirium in older adults: best practice statement from the
American Geriatrics Society. J Am Coll Surg. 2015;220:136-48.e1.
15. Oh ES, Fong TG, Hshieh TT, et al. Delirium in Older Persons: Advances in
Diagnosis and Treatment. JAMA. 2017;318:1161-74.
16. Hesse S, Kreuzer M, Hight D, et al. Association of electroencephalogram
trajectories during emergence from anaesthesia with delirium in the
postanaesthesia care unit: an early sign of postoperative complications. Br J
Anaesth. 2019;122:622-34.
17. Miller D, Lewis SR, Pritchard MW, et al. Intravenous versus inhalational
maintenance of anaesthesia for postoperative cognitive outcomes in elderly
people undergoing non‐cardiac surgery. Cochrane Database Syst Rev.
2018;8:CD012317.
18. Duan, X, Coburn M, Rossaint R, et al. Efficacy of perioperative dexmedetomidine
on postoperative delirium: systematic review and meta-analysis with trial
sequential analysis of randomised controlled trials. Br J Anaesth. 2018;121:
384-97.
19. Wang S, Sigua NL, Manchanda S, et al. Preoperative STOP-BANG Scores and
Postoperative Delirium and Coma in Thoracic Surgery Patients. The Ann Thorac
Surg. 2018;106:966-72.
20. Yang FM, Marcantonio ER, Inouye SK, et al. Phenomenological subtypes of
delirium in older persons: patterns, prevalence, and prognosis. Psychosomatics.
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21. Rudolph JL, Marcantonio ER. Delirium. In: Duthie EH, Katz PR, Malone M
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22. Farrell KR, Ganzini L. Misdiagnosing delirium as depression in medically ill
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25. Fick DM, Inouye SK, Guess J, et al. Preliminary development of an ultrabrief
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26. Steis MR, Evans L, Hirschman KB, et al. Screening for delirium using family
caregivers: convergent validity of the Family Confusion Assessment Method
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29. Feter SH, Dunbar MJ, MacLeod H, et al. Predicting post-operative delirium in
elective orthopaedic patients: the Delirium Elderly At-Risk (DEAR) instrument.
Age and Ageing. 2005;34(2):169-71.
30. Zhang X, Tong DK, Ji F, et al. Predictive nomogram for postoperative delirium
in elderly patients with a hip fracture. Injury. 2019;50(2):392-7.
31. Ayob F, Lam E, Ho G, et al. Pre-operative biomarkers and imaging tests as
predictors of post-operative delirium in non-cardiac surgical patients: a
systematic review. BMC Anesthesiol. 2019;19:25.
32. Inouye SK, Baker DI, Fugal P, et al. Dissemination of the hospital elder life
program: implementation, adaptation, and successes. J Am Geriatr Soc.
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33. Inouye SK, Bogardus ST, Baker DI, et al. The Hospital Elder Life Program: a
model of care to prevent cognitive and functional decline in older hospitalized
patients. J Am Geriatr Soc. 2000;48:1697-706.
34. Hshieh TT, Yang T, Gartaganis SL, et al. Hospital Elder Life Program:
Systematic Review and Meta-analysis of Effectiveness. Am J Geriatr Psychiatry.
2018;26(10):1015-33.
35. Bouhout I, Ellouze M, Cartier R. Preoperative Statins Reduce Postoperative
Delirium Following Off Pump Coronary Artery Bypass. Can J Cardiol. 2018;34:S8.
36. Hudetz JA, Patterson KM, Iqbal Z, et al. Ketamine attenuates delirium after
cardiac surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth.
2009;23:651-7.
37. Robinson TN, Eiseman B. Postoperative delirium in the elderly: diagnosis and
management. Clin Interv Aging. 2008;3:351-5.
38. Han CS, Kim YK. A double-blind trial of risperidone and haloperidol for the
treatment of delirium. Psychosomatics. 2004;45:297-301.
39. Saczynski JS, Marcantonio ER, Quach L, et al. Cognitive trajectories after
postoperative delirium. NEJM. 2012;367:30-9.
40. Hudetz JA, Patterson KM, Byrne AJ, et al. Postoperative delirium is associated
with postoperative cognitive dysfunction at one week after cardiac surgery with
cardiopulmonary bypass. Psychol Rep. 2009;105:921-32.
41. Witlox J, Eurelings LS, de Jonghe JF, et al. Delirium in elderly patients and
the risk of postdischarge mortality, institutionalization, and dementia: a meta-
analysis. JAMA. 2010;304(4):443-51.
Gas Embolism: An Update 99
CHAPTER
7 Gas Embolism: An Update
Anju Romina Bhalotra, Rahil Singh
INTRODUCTION
Vascular air embolism (VAE) refers to the entry of gas into the vasculature,
resulting in systemic manifestations.1 The term gas embolism indicates the
presence of air, oxygen (O2), carbon dioxide (CO2), nitrogen (N2), etc. in the
vasculature due to a pressure difference between the atmosphere and blood
vessels which allows entry of the gas.2 Emboli can be venous, arterial, or
paradoxical and can be distinguished by the likely etiology and the location
of the embolus. The most common type of gas embolism seems to be air
embolism, which is usually iatrogenic in nature. The solubility of the gas and
the volume entrained determine the resulting physiologic effects. A wide
spectrum of clinical presentations may be seen ranging from no/minor
effects to even death.3
Improvements in monitoring indicate that occurrence of a VAE is
relatively common during many surgical procedures1 and recent advances
in surgical and interventional procedures have further increased the risk.
Most episodes are preventable and meticulous precautions and early
detection and proper management can reduce the associated morbidity
and mortality. It is thus necessary for clinicians to know of the etiology and
pathophysiology, predisposing factors, measures for prevention, and clinical
presentation and recognition of VAE, to prompt timely management.
EPIDEMIOLOGY
The true incidence and prevalence of VAE are impossible to ascertain
because asymptomatic patients are often missed, signs and symptoms are
nonspecific, and the diagnosis is difficult to establish. Also, much depends
on the sensitivity of the methods used for detection.
Procedures which carry a high risk (>25%) of VAE include neurosurgical
procedures in sitting position and surgeries on the neck (10–100%),3-6
laparoscopic procedures (69% to 100%),7,8 orthopedic surgeries (57%),9 with
30%5 in total hip arthroplasty, obstetric-gynecological surgeries (11–97%),5,10,11
with 40% in cesarean delivery,5 and related to central venous access,12 and
craniosynostosis repair.13 Procedures with a medium risk (5–25%) include

prostatectomy, laminectomy (cervical spine), spinal fusion, gastrointestinal
endoscopy, contrast radiography, blood transfusions, and cardiac surgery.
There is a low risk of VAE (<5%) reported in surgeries on anterior neck and
peripheral nerves, vaginal procedures, burr hole neurosurgery, and hepatic
surgery.14 Other situations where VAE can occur are in penetrating chest
trauma (7%), barotrauma, and use of a pressure infuser bag.15
ETIOLOGY
Gas emboli are of different types:
• Venous air/gas embolism is presence of air/gas in veins or right side of
the circulation.
• Pulmonary air/gas embolism is said to occur once the embolus reaches
the pulmonary circulation via the right ventricle (RV).
• An arterial air embolism refers to air present in the arterial or left side
of the circulation.
• Paradoxical air embolism (PAE) is said to occur when air crosses from
the venous to systemic circulation.
For air to gain access to the vascular system, there has to be a source
of gas and a pressure gradient to allow its ingress into the vasculature. This
pressure gradient may be passive or active/forced. The volume and rate
of gas entrainment depend upon the caliber of the blood vessel and the
gradient of pressure.
The causes can be:
• Forced air entry associated with the use of pressure infusion bags, and
presence of air in intravenous tubings and syringes.16
• Mechanical positive pressure insufflation in laparoscopic, thoracoscopic,
hysteroscopic, endoscopic, etc. procedures.
• Surgical site higher than the level of the heart, which favors passive
entry of air into an open blood vessel due to the created subatmospheric
pressure. A height greater than 2 inches above the right atrium (RA) is
considered a risk factor.17,18 A similar pressure gradient can be found
when the patient is made prone.19,20 The risk of air entrainment further
increases when veins are noncollapsible like the dural venous sinuses
or when collapse is not allowed as during surgical dissection.
• An iatrogenic pressure difference created by a central venous catheter
(CVC) terminating in the superior vena cava, if the central venous
pressure (CVP) is low.4
• Traumatic injuries to chest and head.1
• Changes in ambient barometric pressures—scuba diving, aviators,
astronauts, and positive pressure ventilation.1
Typically, a gas embolism occurs in an anterograde venous course

but may also occur via the epidural space or in a retrograde manner
through veins or arteries21 and in these cases, air may be found in unusual
compartments.
Arterial air embolism (AE) may occur during angiography, if air is
inadvertently instilled into an artery or as a PAE.
• A PAE often occurs through a probe patent foramen ovale (PFO) which
may exist in as many as 30% patients.3,5
• It may also occur due to transpulmonary passage of air5,22,23 if the amount
of air reaching the lungs is greater than that which can be filtered by the
capillaries in the lungs.24 This physiologic filter becomes overwhelmed
once the rate of air entrainment exceeds 0.3 mL/kg/min.21,25,26
• Pathologic dilation of pulmonary vessels or arteriovenous malformations
in lungs of patients with hepatic disorders or hereditary hemorrhagic
telangiectasia may also cause PAE.26
• Retrograde ascent of air emboli into cerebral veins may occur.27 When a
patient is recumbent, air emboli are directed toward the RA.27 However,
when a patient is upright or the level of the patients head is above
heart level, air can flow in a retrograde manner into the cerebral veins
and an awake patient may hear a “rushing sound” due to air bubbles
ascending through the neck vessels. This is usually observed once the
angle of inclination exceeds 45° and is most obvious at 90°. Usually,
the presence of the internal jugular venous valve prevents the cephalad
flow of blood, but if the valve is incompetent, peripheral venous AE may
reach the cerebral veins.27
PATHOPHYSIOLOGY
The pathophysiologic effects produced by a VAE are like any other pulmonary
embolism. Embolic obstruction of blood vessels causes occlusion of perfusion
distal to the obstruction with increases in pressures in pulmonary artery
and RV, ventilation/perfusion (V/Q) mismatch, intrapulmonary shunting,
and an increase in alveolar dead space. Sudden changes in RV pressure
result in RV strain, with failure of the right heart, fall in cardiac output, RV
ischemia, and arrhythmias leading eventually to cardiovascular collapse.3
Embolization of air into the RV stimulates release of endothelin-1 from the
pulmonary vascular tree leading to pulmonary hypertension.21
Air entering the right heart is prevented from entering the systemic and
coronary vasculature by the filtering action of the vessels of the pulmonary
capillary bed. Also, some amount of air is dissipated across the vast alveolar
surface area.11 Turbulent flow produced in the blood vessels results in
formation of microbubbles, which promote aggregation of platelets and
neutrophils. Platelet aggregation leads to release of enzymes like platelet
activator inhibitor, and a systemic inflammatory response may be initiated,22

while neutrophil aggregation leads to increased vascular permeability. This
along with release of O2 free radicals may result in pulmonary edema with
consequent decrease in lung compliance, hypoxemia, and respiratory
failure.3,21,27
The degree of physiologic impairment and morbidity and mortality
depends upon the amount of gas entrained, its rate of accumulation,
whether it is room air, CO2 or N2O, patient position at time of suspected
embolism, and end location of the embolus.3
In adults, bradycardia and cardiovascular collapse have been seen with
air introduced at rates more than 1.5 mL/kg/min.3 The lethal bolus dose
is postulated to be 3–5 mL/kg and if air is introduced at a slower rates of
about 100 mL/sec, the lethal dose may increase to about 300–500 mL.3 It is
pertinent to realize that introduction of 100 mL/sec of air is possible up to
a lethal volume of 500 mL using a 14 G needle and a pressure difference of
only 5 cm H2O between atmosphere and veins.3,21,24,27-29 Lesser amounts of air
may result in death if the patient is very ill or hemodynamically unstable,28
or when the entrainment site is closer to the right heart.21
The pathophysiologic pathway activated depends greatly on the volume
of gas accumulating within the RV.21
• An air lock phenomenon may occur with a bolus of about 5 mL/kg of air/
gas5,21,30 resulting in complete obstruction to RV outflow, cardiac failure,
and circulatory collapse.
• Lesser amounts result in obstruction to RV outflow, with consequent
decreases in cardiac output and hemodynamic instability leading to
myocardial and/or cerebral ischemia, which may prove to be fatal.5,21
• With slower rates of air entrainment, microemboli enter and obstruct
the pulmonary blood vessels. A mesh of fibrin, globules of fat, red
blood cells (RBCs), and platelets form around the emboli, which attracts
neutrophils and the resultant ultrastructural damage leads to increased
capillary permeability and eventually pulmonary edema.5
• With entrainment of even smaller air volumes, cardiac output may
not be significantly reduced but inflammatory mediator release,
vasoconstriction and bronchoconstriction as a result of air entering the
pulmonary vasculature may lead to increasing V/Q mismatch.5,21
• Still smaller emboli may have no clinical consequences as air is dissipated
and absorbed from the bloodstream.
Arterial emboli result in occlusion of arterioles with resultant distal
hypoxemia and ischemia/infarction, if the collateral blood vessels are
inadequate.1 Gas accumulating in the left ventricle impairs ventricular filling
during diastole, and during systole it may be pushed into the coronary
vessels leading to coronary occlusion.3 Cardiac or cerebral ischemia may
result from the embolization of even a small amount of gas into a coronary
or cerebral blood vessel.
CLINICAL PRESENTATION
The clinical presentation depends upon the type of gas, nature and cause
of embolization, and amount and rate of gas entry; and whether the
embolus is venous or arterial and its location. Also, further air entrainment
may be encouraged in a spontaneously breathing patient who develops a
subatmospheric intrathoracic pressure during inspiration as compared to a
patient on controlled ventilation. The symptomatology is indeterminate, but
cardiovascular, respiratory, and central nervous system effects are usually
seen. The presentation differs in awake patients and those under anesthesia.
While in the awake patient, symptoms may aid in early detection, in the
anesthetized patient, clinical signs, and changes in monitoring parameters
are seen.18
Venous Air Embolism

A small VAE may cause no symptoms. Slower entrainment of larger
amounts of air leads to light headedness, tachypnea, dyspnea, wheezing,
intractable coughing, pain in the chest, and a feeling of foreboding.4 The
release of cytokines and complement reflects the immune response of
the lung to ischemia and results in coughing and tachypnea in the awake
patient.18,31 A “gasp reflex” may be elicited in the awake patient if there is
10% obstruction of the pulmonary vasculature and manifests as dyspnea
due to acute hypoxemia or pulmonary edema and results in further and
more rapid air entrainment leading to apnea, hypoxia, and cardiovascular
collapse.21 Clinical signs include presence of rales, wheezing, reduced lung
compliance, and increased airway pressures.
Cardiovascular symptoms include dyspnea, angina, palpitations,
dizziness, and signs of shock. Brady- or tachyarrhythmias, hypotension, rise
in jugular venous pressures and CVP, and signs of pulmonary edema may
be seen. A classical “mill wheel” or “water-wheel” murmur may be heard,
which is a typical splashing sound, heard on auscultation if air is present
within the heart.28 A sudden fall in end-tidal CO2 (EtCO2), reflects increased
dead space ventilation and intrapulmonary shunting which result in a fall
in oxygen saturation (SaO2).
Central nervous system involvement may occur due to cardiovascular
collapse secondary to a fall in cardiac output leading to decreased cerebral
perfusion or if emboli enter the cerebral arterial circulation by direct
introduction or by paradoxical embolization. Mild cerebral involvement
initially leads to an acute alteration in mentation but may be quickly
followed by development of focal deficits and even frank coma.
Thus, if the VAE is small (<0.5 mL/kg), wheezing, altered mental status,
decrease in EtCO2, increase in end-tidal nitrogen (EtN2), and a fall in SaO2
may be seen. With a medium volume (0.5–2 mL/kg) of gas entrained,
the patient may have breathlessness, hypotension, wheezing, pulmonary

hypertension, right heart strain, raised jugular venous pressure, chest
pain, altered mentation, signs of coronary and cerebral hypoperfusion or
ischemia, and bronchospasm. With larger volumes, (>2 mL/kg), there may
be cardiac failure and circulatory collapse.18
On investigation, electrocardiographic findings include peaking of the
P wave, brady or tachyarrhythmias, atrioventricular block, nonspecific ST–T
changes or ST segment elevation/depression, and a right heart strain. X-ray
chest may be normal after a small embolus or show signs of pulmonary
edema, enlarged pulmonary trunk, atelectasis, or presence of air in heart.
If air is seen in the main pulmonary artery, it is highly suggestive of air
embolism.28 Arterial blood gas analysis reveals a low partial pressure of
oxygen (PaO2), high partial pressure of carbon dioxide (PaCO2), and increased
alveolar-arterial gradient for O2.11 On invasive cardiac monitoring, a rise in
CVP is seen in 25% patients and of pulmonary artery pressures in 50%.5
Echocardiography can quickly detect any air in the heart or great vessels,
chamber dilatation, or pulmonary hypertension.28 Computed tomography
(CT) may reveal air in the major vessels and heart. V/Q scan reveals a V/Q
mismatch when a large embolism occurs, and a rapid resolution of this
mismatch is seen on repeat V/Q scan if done after 24 hours. This helps to
distinguish VAE from other forms of pulmonary thromboembolism.28
Arterial Gas Embolism

This may lead to occlusion of cardiac and cerebral vessels. Air in coronary
arteries leads to angina, hypotension, arrhythmias, cardiac failure, and even
cardiovascular collapse. If air enters the cerebral arteries, the patient may
manifest stroke like symptoms like headache, confusion, disorientation,
altered mental status, focal neurological deficits, seizures, loss of conscious
ness, coma, motor weakness, hemiparesis, etc.
Examination may reveal asymmetrical pupillary responses, impair
ment of vital brain centers, and abnormal respiratory patterns. On
electrocardiography, signs of myocardial ischemia/infarction may be seen.
Retinal examination may reveal gas bubbles while CT/magnetic resonance
imaging (MRI) may show the presence of hypodense lesions/intracerebral
air with or without infarction.
DETECTION
Awareness of the likelihood of VAE during a high-risk procedure is essential
for early detection and diagnosis and it must be suspected early in patients
with sudden decompensation and with obvious risk factors for the same.28
Monitors used to detect intravascular air should have a high sensitivity,
be simple to use, and non-invasive. The choice of monitor should be
determined by the anticipated risk of embolism during the procedure.
Various monitoring modalities are as below:

• Transesophageal echocardiography (TEE) is highly sensitive, with
the ability to detect 0.02 mL/kg air or bubbles of the size of 5–10
microns.1,21,32 It can quantify the amount of air22 and detect venous
macro- and microemboli and PAE. However, it may be overly sensitive,
detecting almost any air, most of which may not have adverse sequela.
But, the detection of even very little air can warn the anesthesiologist
to take immediate precautions to reduce any further entrainment.
TEE is invasive and may cause glottic or esophageal injury. It is also
cumbersome, expensive, and requires constant vigilance, expertise, and
intensive training for interpretation.
• Precordial Doppler ultrasound is less sensitive than TEE but is non-
invasive. It can detect 0.05 mL/kg or 0.25 mL air.21,30 The Doppler probe,
if placed along the border of the right heart, can receive signals from
the RV outflow tract. Correct probe position can be confirmed by a
“bubble test”, which requires the injection of less than 1 or 1 mL of air
in 9 mL saline, and a VAE is indicated by a characteristic change in
the emitted sound.21 While normal blood flowing through the cardiac
chambers creates a turbulent resonance, a high-pitched swishing roar
is superimposed in the presence of a VAE.21 With entrainment of larger
volumes, a more potentially dangerous “drum-like” or “mill wheel”
murmur develops indicating cardiovascular decompensation. However,
there may be sound artifacts with use of electrocautery and difficulty in
using in prone and lateral positions and in the morbidly obese patient.30
• End-tidal nitrogen (ETN2) is a sensitive monitor, measures increase in
ETN2 of 0.04%,21,30 can detect as little as 0.2–0.3 mL/kg of air11 and has
an absolute specificity for air emboli. Emission spectrometry can also be
used to detect ETN2 levels as an alternative to mass spectrometers and
is more sensitive, detecting 0.1 mL/kg.11 Changes in ETN2 occur 30–90
seconds earlier than changes in EtCO2.11,21 However, ETN2 is neither
routinely available, nor is useful if N2O is used as a carrier gas. The
method is limited during hypotension and is expensive.
• End-tidal CO2 is non-invasive and easily available. There is a sudden
decrease in EtCO2 levels in event of VAE and it has a sensitivity of
0.5 mL/kg.22 A fall of 0.2% or even 2 mm Hg below the baseline can
indicate a VAE.11,30 EtCO2 monitoring is, however, not very specific
and may be unreliable in spontaneously breathing patients and in the
presence of systemic hypotension, obstruction of the airway, or mouth
breathing or when the respiratory rate is very variable. The gas analyzer
port can be obstructed by secretions or water vapor.
• Pulmonary artery catheter (PAC) detects 0.5 mL/kg of gas/air in 80%
of bolus injections when a rise in pulmonary artery pressure by 25% is
defined as a positive sign of VAE.11 It is relatively insensitive, nonspecific,
and invasive, inferior to the precordial Doppler but slightly more

sensitive than EtCO2. There is a limited ability to withdraw air from its
small caliber lumen. The use of a PAC is restricted to those patients who
benefit from its use as a monitoring tool for cardiac output or mixed
venous saturation.
• Central venous catheter has a poor sensitivity and specificity but is cheap
and widely available and aids in aspiration of air if VAE is suspected.
There are risks of trauma on insertion and it may itself be a source of
VAE.
• Pulse oximetry is not very useful as fall in SaO2 usually occurs late and
is a nonspecific sign.
• Transcranial Doppler ultrasound is highly sensitive and has been used
as a screening tool to detect a PFO in patients undergoing procedures
at high-risk for AE. The use of the Valsalva maneuver increases its
sensitivity and it can detect 0.05 mL/kg air.22
• Stethoscopes, esophageal or precordial, have a poor sensitivity in detecting
VAE which is indicated by auscultation of a mill wheel murmur, i.e.
1.7 mL/kg/min21,22 and 1.5 mL/kg/min,22 respectively. Stethoscopes are
widely available and cheap. However, use requires constant supervision
and provides little warning of cardiovascular collapse.
• Electrocardiographic changes have a low sensitivity to detect VAE, and
usually occur with only larger emboli.
• Clinical signs and observation of respiration have a poor sensitivity and
specificity and are late indicators.
DIFFERENTIAL DIAGNOSIS
Other likely causes of a sudden respiratory, cardiovascular or cerebral
compromise should be considered and excluded by careful history, exami
nation, and investigations. Differential diagnoses include thromboembolism
(pulmonary, cerebral, and coronary), bronchospasm, acute coronary
syndrome, pneumothorax, pleural or pericardial tamponade, pulmonary
edema, different types of shock, cerebrovascular accident, and metabolic
causes (hypoglycemia).16
PREVENTION
Patients undergoing interventions with high risk of AE should be identified
and preventive measures should be applied which include the following:
• Maintaining meticulous hemostasis by careful surgical technique to
prevent opening of veins and ensuring that the venous circulation is
open to the atmosphere for the shortest time.
• Reducing the height difference between the surgical field and RA.
• Decreasing the pressure difference between open veins in the operative

field/site of intervention and the RA by maintaining CVP above 10 cm
H2O.33 This can be achieved by:
▪▪ Use of leg elevation.
▪▪ Compression of jugular veins at those times when the risk of an
embolism occurring seems high.
▪▪ Ensuring adequate hydration.
▪▪ Positive end-expiratory pressure (PEEP): However, in patients being
operated in the “sitting position”, the PEEP levels required to elevate
CVP sufficiently to prevent VAE are very high and may cause
cardiovascular instability.30 Also, application or release of PEEP may
potentially increase risks of PAE if the patient has a PFO, by increasing
RA pressures above left atrial pressures.5,30,34 Thus PEEP should be
applied very carefully and as a means to increase oxygenation and
not as preventive measure for VAE.21 There is insufficient evidence to
suggest any benefits of using high values of PEEP.
▪▪ Use of military antishock trousers (MAST)—by maintaining
MAST pressures above 50 cm H2O in the lower compartment, an
autotransfusion of about 750–1,000 mL blood30 can be achieved which
increases right atrial pressure (RAP) above atmospheric pressure.11,21,34
Its routine use is not justified.
• Avoid use of N2O: As N2O is far more soluble in blood as compared to N2
(34 times), its use may markedly increase the size of an air embolus.21
In cases at high risk of AE, it may be prudent to avoid the use of N2O
and it should be used in other procedures only if the benefits of its use
outweigh the potential risks.21,30
• Ensure all vascular catheters and intravenous administration sets are
purged of air.
• Insert CVC in high-risk cases: Ensure proper position (the catheter tip
should lie 2 cm further than the junction of RA and superior vena cava)
guided by ultrasound, X-ray chest, or electrocardiogram (EKG) lead on
CVC (development of large negative P complex).21
MANAGEMENT
Once a VAE is strongly suspected, it is necessary to institute immediate
management as follows:
• Prevent further air entrainment:
▪▪ Inform the surgeon who can flood the operative site with saline and
assess and eliminate any possible air entry sites.
▪▪ Conduit between the atmosphere and vasculature must be identified
and closed, and the wound edges should be compressed.
▪▪ The operating site/likely site of air entry should be lowered. For

surgical procedures below heart level, the patient may be put in the
head up position.
▪▪ Peritoneal desufflation should be done during laparoscopic
procedures.
▪▪ The CVP should be elevated by intravenous fluid loading, PEEP,
MAST,21 etc. Valsalva maneuver increases intrathoracic pressure and
reduces venous return.
▪▪ In intracranial surgery, transient compression of jugular veins leads
to an increase in venous pressures resulting in a retrograde flow
and helps identify open dural sinuses. However, jugular venous
compression may increase intracranial pressure and reduce cerebral
perfusion. It may also cause inadvertent compression of the carotid
artery and decreased cerebral perfusion, cerebral edema due to venous
engorgement, carotid sinus stimulation with severe bradycardia, and
may dislodge any atheromatous plaques.30
• Administer O2 and discontinue N2O:
▪▪ Increase in PaO2 favors N2 washout and helps to reduce embolus
size.21
▪▪ Nitrous oxide diffuses rapidly into the air bubble and increases its
size.21 Air does not get absorbed very quickly after a VAE and an
embolus may expand, if N2O is restarted.21
• Change patient position to reduce embolic obstruction:
▪▪ In Durant’s maneuver, the patient is placed in the left lateral position
with a Trendelenburg tilt so that any gas/air floats out of the RV
outflow tract thereby relieving the “air-lock” which may lead to
cardiorespiratory collapse.3,28,35
▪▪ In the hemodynamically unstable patient, the Trendelenburg position
has been suggested.21
▪▪ Recent studies have questioned the role of Trendelenburg and left
lateral positions in improving hemodynamic performance.21,27,35 The
concept of repositioning patients after a suspected VAE has been
questioned in animal studies but there is insufficient data in humans.21
▪▪ In event of a cerebral AE due to a retrograde embolism or PAE, the
Trendelenburg position may further increase intracranial pressure
and exacerbate any cerebral edema and the patient should remain
supine. Also, in paradoxical cerebral AE, the Trendelenburg position
is ineffective in preventing propulsion of air bubbles into the cerebral
circulation.27,28
• Assure hemodynamic support:
▪▪ Aggressive fluid resuscitation and vasopressors are often needed to
optimize myocardial perfusion and provide inotropic support to the
RV.21,27
• Cardiopulmonary resuscitation (CPR):

▪▪ Early CPR with defibrillation and chest compression is indicated in
massive VAE resulting in cardiac arrest.
▪▪ Even without indication for CPR, chest compressions may help
breakdown larger air/gas emboli and force them out of the RV and
into the pulmonary tree, thereby facilitating forward blood flow and
an improvement in cardiac output.21,28,35
• Aspirate air from the RA:
▪▪ The average amount aspirated in various reports is 15–20 mL.21,30
▪▪ There is insufficient data to suggest insertion of a CVC to aspirate air
during an acute episode of VAE.21
• Hyperbaric oxygen therapy (HBOT):
▪▪ Hyperbaric oxygen therapy provides 100% O2 at pressures above the
atmospheric pressure and enhances the PaO2, provides O2 to ischemic
organs, constricts pathologic air bubbles, and diminishes gas volume
and cerebral edema.1,21,35,36
▪▪ It is beneficial if instituted within 6 hours after an AE but there are
some reports of benefit with delayed HBOT.21
▪▪ At present, HBOT is not routinely used in all patients with AE. The
indications are limited and there are problems associated with
transportation of a hemodynamically unstable patient to the HBOT
chamber and duration of the HBOT required.
• Experimental therapies:
▪▪ Fluorocarbons may increase the reabsorption of bubbles and the
solubility of gases in blood and have been used to reduce the
complications of VAE, especially when there is cerebral ischemia.21,37
SPECIAL SITUATIONS
Traditionally VAE has been recognized as a frequently potentially life-
threatening event in patients undergoing surgery in the “sitting position”. It
is necessary to remember that this life-threatening complication can also
occur in a variety of other surgical and interventional procedures.
Cesarean Delivery
The 15° left lateral tilt during surgery creates a gradient between the RA, and
the uterus, promoting entrainment of room air.21 Risk factors are head down
table position, antepartum hemorrhage, uterus exteriorization, manual
removal of placenta, pre-eclampsia, and a volume depleted patient.11 The
highest risk seems to be during uterus exteriorization and placing the
patient in the head up position does not lessen this complication.38
Hysteroscopy
During operative hysteroscopy, the high volumes of irrigation fluid and
extensive cervical dilatation (which may cause cervical lacerations)
predisposes to air embolization. The cervix should not be exposed to air
after dilatation, and vagina should be packed with a dilator/wet gauze
between dilatations39 as the pressure gradient between the endometrial
cavity and RA can cause air to enter the uterine veins if patient is placed
in Trendelenburg position. Hence, Trendelenburg’s position should not be
given at any time.39 Repeated introductions of the hysteroscope and use of
irrigation fluid may facilitate entry of debris, blood clots, and air bubbles
into open uterine sinuses.40 The bubbles produced by tissue vaporization
may also enter open venous channels.39 To minimize this, uterine distension
pressures should be reduced to minimum required (50–100 mm Hg).39 The
use of N2O during these procedures remains debatable.
Prone Position
In the prone position, it is necessary to ensure that the patient’s abdomen is
free. However, this also results in the veins in the epidural space becoming
relatively empty and subatmospheric pressures have been recorded in the
inferior vena cava,19 predisposing to venous AE.20,41
During Insertion and Removal of CVC’s

Central venous catheterization carries high risk of air embolism. Precautions
to prevent this from occurring include:
• Correct factors leading to a low CVP27 (volume deficit, widespread
systemic vasodilatation, etc.)
• Use Trendelenburg position during insertion and removal of the CVC.
• No coughing or talking while removing or placing the CVC.
• Ensure needle hub and catheter are occluded when not in use,21 there
are no cracks/broken seals in catheter and its connections, and all air
is expelled from syringes.
• Prevent accidental catheter misplacement/removal.
• During removal, ask patient to perform Valsalva maneuver to increase
the CVP,21,27 or temporarily hold breath in full inspiration.27
• Apply PEEP if patient is on mechanical ventilation.
• Occlude entry site with an impermeable dressing after removal as a
residual subcutaneous tract can allow air entry.27
Children Undergoing Craniectomy in Supine Position13

Relatively larger head size leads to unintentional positioning of operative
site above RA. In addition, the infant scalp is highly vascular and rapid
blood loss leads to low CVP. Hypotension with VAE may be more profound
as volume of entrained air is greater as compared to their cardiac volume
and the site of entrainment is close to heart due to small body size. Almost
half the children with ages below 5 years may have PFO with higher chances
of PAE.
CO2 Embolism in Laparoscopy

Carbon dioxide is the most widely used gas for insufflation and CO2 emboli
occur due to direct vascular injection through a misplaced needle or trocar,
or as a result of injury to organ parenchyma during insufflation.42,43 A
continuous intravenous CO2 infusion at 1.2 mL/kg/min (5% of the volume
that can be infused through a misplaced Veress needle) was found to have
a mortality of 60%.44 Others have reported lower mortality rates (28%).43,44
Smaller amounts may enter the bloodstream when vessels in the wall of
the abdomen or surgical site are injured.23,44 During peritoneal insufflation,
as intra-abdominal pressures rise, any injured veins in the abdominal
wall collapse and terminate the embolic episode.23 During laparoscopic
cholecystectomy, gas entering the hepatic circulation, initially gets trapped
in the liver. However, higher amounts may bypass the liver filter leading to
an air lock.23
Carbon dioxide has a high blood solubility and therefore, is rapidly
eliminated. The effects of a CO2 embolism are thus, similar to, but less
marked than those of air. Also, CO2 emboli do not lead to bronchospasm
or fall in lung compliance.44
Embolism should be considered whenever a sudden hemodynamic
compromise with fall in EtCO2 occurs after CO2 insufflation.23 Risks are
higher when the operative site is elevated,42 in presence of numerous venous
channels, like primary biliary cirrhosis,43 or unanticipated anatomical
variations (patent paraumbilical vein).
Capnography may show an initial rapid rise and then a fall in
EtCO2. If embolism is suspected, insufflation should be stopped, and
pneumoperitoneum released.44
Hyperventilation with 100% O2 does not reduce CO2 embolus size very
significantly as the solubility of N2O and CO2 in blood is similar. Similarly,
HBOT may be considered but is less effective than for air emboli.44
Preventive measures include ensuring proper placement of Veress needle,
minimizing needle manipulations, maintaining low insufflation pressures,44
and avoiding hypovolemia.
CONCLUSION
Vascular air embolism may occur in many of the clinical situations
encountered by an anesthesiologist. In most of the cases, VAE is iatrogenic
and is preventable. It is necessary to be very vigilant in high-risk situations
and adopt suitable precautions and monitoring to prevent and detect VAE,
which may lead to considerable morbidity and, maybe even, mortality. In the
event of suspected VAE, appropriate management should be instituted, and
CPR may even be required. With the increasing variety of surgical procedures
in operation theatres and radiological suites, all anesthesiologists need to
be familiar with the risk factors, clinical features, detection, prevention, and
management of a VAE.
KEY POINTS
• Vascular gas embolism refers to the entry of a gas into the vasculature,
resulting in systemic manifestations. Emboli may be venous, arterial, or
paradoxical.
• Carbon dioxide emboli may occur during gas insufflation because of
accidental intravascular placement of the needle/trocar or injury to organ
parenchyma.
• Risk factors for gas emboli include site of surgery about 2 inches (5 cm)
higher than the heart level and a pressure difference allowing gas/air to
enter the vasculature.
• The clinical signs and symptoms are dependent on the volume and site
of the embolus.
• Prevention is by careful intraoperative patient positioning, adequate
hydration, limiting use of nitrous oxide, and due precautions during
handling of vascular catheters.
• While transesophageal echocardiography is reported to have the highest
sensitivity to identify gas in the vasculature, capnography is routinely
available, simple, and detects most emboli likely to cause clinical sequela.
• Once gas embolism is suspected, immediate and timely management is
important to reduce poor patient outcomes.
• Further entrainment of air/gas should be stopped and hemodynamics
optimized by instituting cardiopulmonary resuscitation if required. The
mainstay treatment for significant VAE is hyperbaric oxygen therapy.
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28. Sviri S, Woods WP, Heerden PVV. Air Embolism—A Case Series and Review.
Crit Care Resusc. 2004;6:271-6.
29. Natal B, Doty CI. (2014). Venous Air Embolism Clinical Presentation; 2014.
[online] Available from: http://emedicine.medscape.com/article/761367-
clinical [Last accessed August, 2019].
30. Khan ZH, Samadi S, Zanjani AP, et al. Air embolism in sitting position
during neurosurgical operations and its prevention: A narrative review. Arch
Anesthesiol Crit Care. 2019;5(2):54-61.
31. Moitra V, Permut TA, Penn RM, et al. Venous air embolism in awake patient
undergoing placement of deep brain stimulators. J Neurosurg Anesthesiol.
2004;16:321-2.
32. Jaffe RA, Siegel LC, Schnittger I, et al. Epidural air injection associated with
air embolism detected by transesophageal echocardiography. Reg Anesth.
1995;20:152-5.
33. Domaingue CM. Anaesthesia for neurosurgery in the sitting position: a practical
approach. Anaesth Intensive Care. 2005;33(3):323-31.
34. Meyer PG, Cuttaree H, Charron B, et al. Prevention of venous air embolism
in paediatric neurosurgical procedures performed in the sitting position by
combined use of MAST suit and PEEP. Br J Anaesth. 1994;73:795-800.
35. McCarthy CJ, Behravesh S, Naidu SG, et al. Air Embolism: Practical Tips for
Prevention and Treatment. J Clin Med. 2016;5(11):93.
36. Blanc P, Boussuges A, Henriette K, et al. Iatrogenic cerebral air embolism:
importance of an early hyperbaric oxygenation. Intensive Care Med.
2002;28(5):559-63.
37. Eckmann DM, Lomivorotov VN. Microvascular gas embolization clearance
following perfluorocarbon administration. J Appl Physiol. 2003;94:860-8.
38. Karuparthy VR, Downing JW, Husain FJ, et al. Incidence of venous air embolism
during cesarean section is unchanged by the use of a 5 to 10 degree head-up
tilt. Anesth Analg. 1989;69(5):620-3.
39. Verma A, Singh MP. Venous gas embolism in operative hysteroscopy: A
devastating complication in a relatively simple surgery. J Anaesthesiol Clin
Pharmacol. 2018;34:103-6.
40. Leibowitz D, Benshalom N, Kaganov Y, et al. The incidence and haemodynamic
significance of gas emboli during operative hysteroscopy: A prospective
echocardiographic study. Eur J Echocardiogr. 2010;11:429-31.
41. Mahajan C, Rath GP, Sharma VB, et al. Venous air embolism during release of
tethered spinal cord in prone position. Neurol India. 2011;59:777-8.
42. de Jong KIF, de Leeuw PW. Venous carbon dioxide embolism during laparoscopic
cholecystectomy a literature review. Eur J Intern Med. 2019;60:9-12.
43. Cadis AS, Velasquez CD, Brauer M, et al. Intraoperative management of a
carbon dioxide embolus in the setting of laparoscopic cholecystectomy for a
patient with primary biliary cirrhosis: A case report. Int J Surg Case Reports.
2014;5:833-5.
44. Park EY, Kwon JY, Kim KJ. Carbon dioxide embolism during laparoscopic
surgery. Yonsei Med J. 2012;53(3):459-66.
Nutrition in the Intensive Care Unit 115
CHAPTER
8 Nutrition in the Intensive

Care Unit
Richa Aggarwal, Kapil Dev Soni
INTRODUCTION
Nutritional therapy in the intensive care unit (ICU) refers to provision of
either enteral nutrition (EN) or parenteral nutrition (PN) to the patient.1 It
includes provision of all nutrients including carbohydrates, proteins, fats,
vitamins, minerals, and trace elements in adequate dosages. Nutrition in
critically sick patient is of paramount importance. Critical illness poses a
major catabolic stress in the patient and predisposes to various infections.
Adequate supplementation of nutrients to ICU patients is not just supportive
therapy but has significant therapeutic value and may affect the outcome
of the patients.1 Nutritional therapy moderates and restores physiological
immune response to critical illness. The total amount of energy deficit in
the critically ill patients is associated with prolonged length of ICU stay,
increased risk of infection and risk of death. Timely initiation of optimum
nutritional therapy is required to halt the ongoing catabolic process and
decrease this risk. Despite this, there are many lacunae while prescribing
adequate nutrition to patients. A study evaluating nutritional practices
in 20 countries found significant deficiencies in meeting the nutritional
requirements of patients.2
Nutritional requirements vary among critically ill patients. The quantity
and quality of nutrition intake have to be individualized for these patients.
Moreover, the needs of an individual also vary according to the severity of
illness, physiological stress, and the state of illness. The requirements may
not be the same throughout the critical period. There are two phases of
critical illness—(1) the acute phase and (2) the recovery phase.3
1. The acute phase is further divided into two periods—early period, which
is a phase of catabolism and metabolic instability and the late period
characterized by stabilization of metabolic issues but has significant
muscle wasting.
2. Recovery phase is characterized by phase of anabolism.
Adequate feeding is important in both the phases. Hypocaloric feeding is
initiated in the acute phase after hemodynamic stabilization and gradually
increased to the target level (isocaloric feeding) in the recovery phase.
ASSESSMENT OF NUTRITIONAL STATUS

Assessment of nutritional status is difficult in the ICU. The risk of malnutrition
depends on the baseline nutritional status of the patient and the severity
of disease. Anthropometry is not considered reliable for assessment of
nutritional status.1 Weight change also is not regarded as a good indicator as
weight changes may occur due to fluid administration, fluid shifts, edema,
and wasting of lean tissues.3 Albumin and prealbumin levels, once thought
as markers, are not considered good indicators of nutritional status, as
these values can vary in response to inflammation.4 Other markers like
C-reactive protein, interleukin-1, tumor necrosis factor alpha (TNF alpha),
and interleukin 6 are still under investigation.1 There are other screening
and assessment tools available like the Mini Nutritional Assessment, the
Malnutrition Universal Screening Tool (MUST), the Short Nutritional
Assessment Questionnaire, and the Malnutrition Screening Tool5 but no tool
has been validated in ICU. The two tools that determine nutritional status
and disease severity in the ICU are Nutrition Risk Screening 2002 (NRS
2002) and Nutrition Risk in Critically Ill (NUTRIC) score (Appendix 1).1
Recent European Society for Clinical Nutrition and Metabolism (ESPEN)
guidelines3 recommend that a general clinical assessment should be
performed to assess malnutrition. This includes general assessment of body
composition, physical examination, and assessment of muscle mass as well
as strength. Evaluation of lean body mass can be done by ultrasonography
(USG) or computed tomography (CT) scan.6 USG is a promising upcoming
modality to measure muscle mass at bedside.7,8 CT scan can more
precisely quantify skeletal mass but is an expensive modality. Muscle mass
can also be evaluated by bioelectric impedance9 or stable isotopes. In a
conscious patient, muscle function can be evaluated by tools like handgrip
dynamometer.10
PATIENTS AT RISK OF MALNUTRITION

Any patient, who is critically ill and is admitted in the ICU for more than
48 hours, is considered to be at risk of malnutrition. Society of Critical
Care Medicine (SCCM) and American Society for Parenteral and Enteral
Nutrition (ASPEN)1 recommend NRS 2002 and NUTRIC score for assessing
nutritional status, however, recent ESPEN guidelines3 suggest that nutritional
risk screening (NRS) 2002 and MUST11 are easiest to calculate and have the
strongest predictive value for mortality.
INITIATING NUTRITION
Early nutrition therapy should be considered for all patients admitted to the
ICU for more than 48 hours and it should be started within 48 hours.12 The
most preferred way of providing nutrition in the ICU patients is by the oral
Box 1: Contraindications to enteral nutrition.

•• Worsening shock
•• Worsening hypoxemia and acidosis
•• Refractory upper gastrointestinal bleeding
•• Gastric aspirate > 500 mL/6 hours
•• Gut ischemia
•• Bowel obstruction
•• Abdominal compartment syndrome
•• High output fistula without distal feeding access
Box 2: Benefits of enteral nutrition.

•• Maintains the tight junctions between the epithelial cells of gut mucosa
•• Stimulates blood flow to the gut
•• Induces the release of gastrin, cholecystokinin, and bile salts
•• Supports IgA producing immunocytes (gut associated lymphoid tissue)
•• Modulates the systemic immune response
diet. If patients are unable to take orally, then EN is the preferred route of
nutrition. However, if there are immediate contraindications for EN (Box
1), then nutritional therapy depends on the previous health status of the
patient. In nonmalnourished previously healthy patient, EN can be delayed,
whereas in malnourished patients, early PN should be started.3 The benefits
of EN are tabulated in Box 2.
EARLY ENTERAL NUTRITION VERSUS DELAYED

ENTERAL NUTRITION VERSUS PARENTERAL NUTRITION
Various studies have demonstrated significant reduction in infectious
complications in early EN group as compared to delayed EN.3,12 Similarly,
reduction in ICU infections, shorter ICU stay and shorter hospital length of
stay, has been reported in EN group when compared with group receiving
PN.13 However, there is no mortality benefit in EN versus PN group.14,15
Earlier, there were some reservations about starting early EN in patients
with gastrointestinal surgery, aortic surgery, and pancreatitis but now
guidelines recommend to start early EN in such cases.12 The EN should also
be administered in patients receiving neuromuscular blockade, patients in
prone position, and in patients on extracorporeal membrane oxygenation
(ECMO).3,12 The important thing while initiating nutrition is that feeding
in critically ill patients should be gradual. The estimated energy and protein
goal should be achieved in incremental steps and not within first 48 hours.3
Full EN or PN should be prescribed over 3–7 days.
The complications associated with EN are aspiration of intestinal
contents, diarrhea, metabolic abnormalities, and mechanical complications.
ENERGY AND PROTEIN REQUIREMENT OF

CRITICALLY ILL PATIENTS
The first step in initiating nutrition is to calculate the energy and protein
requirements for the patient. These can be determined either by simple
formulas, published predictive equations, or indirect calorimetry (IC).1 IC
is the most accurate. There are around 200 predictive equations1 published;
e.g. the Harris-Benedict, the Frankenfield, the Ireton–Jones, or the Fusco
with the accuracy ranging from 40–75% when compared with IC.16,17
The resting energy expenditure (REE) of a critically ill patient is similar
to that of a normal person. The best-recommended method to measure REE
both by ASPEN1 and ESPEN3 is IC. However, it is not being used frequently
due to nonavailability at all places and due to the cost involved. According
to the recent ESPEN guidelines, if IC is not available, then calculation of REE
should be done from the volume of carbon dioxide breathed out (VCO2)
obtained from ventilators with the equation:3
REE = VCO2 × 8.19
If nothing is available, then simple weight-based equations can be used.
REE = 25–30 Kcal/kg/d
Weight of the patient for calculations of feeding requirement is calculated
from ideal body weight and not actual body weight. The REE achieved may
be multiplied by a factor of 1.2 in cases of mild stress, and by 1.9 in a severe
hypercatabolic state.
For the first few days of critical illness, feeding lower calories compared
to full calories is beneficial.3 Hypocaloric feeding is associated with less
gastrointestinal intolerance. Early full targeted feeding can cause overfeeding
as there is endogenous energy production as well and it also augments the
risk of refeeding syndrome in certain group of patients.
Approximately 70% of the estimated energy requirements should be
provided in the early phase and then, after 3 days, it can be increased to
80–100%. In a study comparing hypocaloric feeding with normocaloric
feeding, the authors demonstrated decreased infection rate in hypocaloric
group.18 However, similar results were not achieved in another important
trial permissive underfeeding versus target enteral feeding in adult critically
ill patients (PermiT Trial) which evaluated low calorie feeding (40–60% of
calorie requirement) with standard feeding (70–100% of calorie requirement).
There was no difference in mortality, infectious complications and length of
hospital stay between the two groups.19 Later, Marik and Hooper in a meta-
analysis20 reported lower hospital mortality in patients with low calorie
feeding versus normocaloric feeding.
The protein requirement needs to be determined separately from the
energy requirements. It is variable during the critical illness depending on
the phases of illness. Protein requirement may vary from 0.8–1.2 g/kg to
1.5–2.0 g/kg body weight. The requirement of proteins increases with the
severity of illness. High protein EN (1.2–2 g per kg of ideal body weight
per day) is recommended by various guidelines.1,3 There is a huge evidence
that adequate protein supplementation improves survival in critically ill
patients.21-23 A large number of studies have been conducted with different
combinations of protein and calorie intake in critically ill patients but the
high protein diet is beneficial only if associated with adequate calories.3
HOW TO PROVIDE ENTERAL NUTRITION?

Patients who are critically ill exhibit varying degrees of gastrointestinal
dysfunction and its incidence ranges from 30% to 70%.1 Enough data exist
that bowel sounds or features of bowel motility like passing of flatus or stool
are not essential before starting of EN as was earlier advocated.
The standard approach to start EN is through gastric access either with
orogastric or nasogastric tube. The position of the tube should be checked
and confirmed radiographically before it is used.24 However, in patients
at high risk of aspiration or intolerance to EN, postpyloric feeding should
be used.1 Davis et al. in a large multicentric trial compared gastric versus
small bowel EN and found no difference in clinical outcomes between the
two groups.25 Other alternative approaches available include percutaneous
endoscopic gastrostomy (PEG) or surgical gastrostomy.
In some group of patients, if there is intolerance to EN, trophic feeding
can be started initially. Trophic feeds are small quantity of feeds given at
the rate of 10–20 mL/hour or 10–20 kcal/hour and are sufficient to prevent
mucosal atrophy and maintain gut integrity.1
Dosing of Enteral Nutrition

Dosing of EN depends on three factors:
1. The nutritional status of the patient
2. Risk of malnutrition
3. Disease severity.
Patients who have adequate baseline nutrition status, who are at low
risk of malnutrition and whose disease severity is low, i.e. patients with
NRS 2002 ≤3 OR NUTRIC score <5, do not require specialized nutrition in
the first week of hospitalization,1 however, they should be reassessed daily
for worsening of disease severity and changing metabolic needs. Patients
who are at high nutrition risk (NRS 2002 ≥5 OR NUTRIC score ≥5), who
are already malnourished should be provided adequate nutrition as early
as possible within 24–48 hours.26,27 Caution should be exercised regarding
refeeding syndrome.
There are various formulations available for EN depending on the
number of calories, the proteins, vitamin and mineral content, and also
the osmolarity. These formulations may be:
• Intact or predigested
• With or without fiber
• With disease specific nutrient.
The standard EN has caloric density of 1 kcal/mL with protein content
of 40 g/1,000 mL and nonprotein calorie to nitrogen ratio of around 130.
There are concentrated feeds available that can be used in patients who
require volume restriction. The calories delivered in EN must be around
50% of calories as carbohydrates and 30% as fat.
Predigested EN has short-chain peptides instead of proteins, simple
form of carbohydrates and decreased fat amount with large proportion
of medium-chain triglycerides. Predigested feed has no advantage over
standard EN and therefore it is not recommended worldwide.28
Feeding can be given either as bolus administration or as continuous
infusion. Latest guidelines of ESPEN recommend continuous rather than
bolus EN as there is better tolerance and decreased incidence of diarrhea
with continuous as compared to bolus administration of EN.3 If the patients
are unable to tolerate gastric feeding, the prokinetics like erythromycin or
metoclopramide can be added. The dose of erythromycin is 100–250 mg
three times a day and should be given for not more than 3 days.29 Adverse
effects of erythromycin include cardiac toxicity, tachyphylaxis, and bacterial
resistance. Alternatively, metoclopramide can be added in the dosage of
10 mg TDS. The side effects of metoclopramide include tardive dyskinesia
especially in the elderly. Both are associated with prolongation of QT
interval.
Continuous monitoring of gastric residual volume is not required for
EN. Only when residual volume is more than 500 mL/6 hours, then feeding
can be delayed. The optimal amount of feeding estimated is 70–100% of
measured energy expenditure as the evidence states that there is reduction
in mortality with this much calorie intake. Underfeeding and overfeeding
are both deleterious for the critically ill patient.30 If the patients are unable
to tolerate full EN during the first week of ICU stay or the EN is not able to
meet >60% of energy and protein requirements, then PN should be added
to EN. ASPEN/SCCM recommends that PN should be added only after 7–10
days of EN.1
Absorption of fat is impaired in critical illness and has to be kept in
account. Mixture of fatty acids should be administered including medium-
chain triglycerides, monounsaturated fatty acids, and polyunsaturated fatty
acids. The upper limit of glucose to be administered is 5 mg/kg body weight
and for lipid is 1.5 g/kg/day.
The only problem with EN is the risk of aspiration and development
of ventilator-associated pneumonia (VAP). The two strategies to decrease
this risk are elevation of the head end of the bed to 30–45° at the time of
feeding31 and chlorhexidine mouthwash twice a day.32
Diarrhea is also common in ICU with the incidence ranging from 2%

to 95%. It may result in electrolyte imbalance, dehydration, and can lead
to bedsores after perineal skin breakdown.33 EN should not be interrupted
for diarrhea but in fact, it should be continued while evaluating its etiology
(infectious diarrhea/osmotic diarrhea) and appropriate treatment should be
started.
PARENTERAL NUTRITION
Parenteral nutrition may be delivered either through a central line or
peripheral line. There are two kinds of preparations available:
1. Preparations for central line which have high osmolality
2. Preparations for peripheral line with low osmolality.
For short duration, the central line preparations can be administered
through central catheters or peripherally inserted central catheters, but
long-term PN requires tunneled central venous catheters.
Components of Parenteral Nutrition

The components of total PN (TPN) solutions are dextrose solutions, amino
acids, and lipids.
• Dextrose is available in 40, 50, and 70% concentrations. The calories
delivered by dextrose are 3.4 kcal/g.
• Amino acids consist of essential and nonessential amino acids. The
concentration of amino acids 5–15%. The calories delivered through
amino acids are 4 kcal/g.
• Lipids are in the form of emulsions. Either they have to be given separately
or can be mixed to the amino acids and carbohydrate components at the
time of delivery to the patient. Lipid emulsions are derived from soya
bean oil, saffron oil, or refined olive oil. The calories delivered are 10–11
kcal/g. Lipid emulsions based only on soya bean oils (rich in omega 6
fatty acids) should be avoided. Lipid emulsions that are based on olive
oil, fish oil, and coconut oil should be added and are advantageous.34
Different studies have demonstrated decrease in length of stay in ICU
and decrease in infection rate with fish oil, and mixed chain triglycerides
as compared to soya bean oil based preparations.35
Vitamins and trace elements must be provided along with PN to prevent
deficiency. A daily-recommended dosage is required. Comparison of
different PN solutions available is listed in Appendix 2.
Strict monitoring is required during PN administration. This includes
fluid intake/output, serum electrolytes, glucose, calcium, magnesium, and
phosphorus daily. Liver enzymes and bilirubin also need to be monitored
depending on the illness state. The complications associated with PN are
tabulated in Box 3.
Box 3: Complications of parenteral nutrition.

Bloodstream infection (bacterial and fungal)
Metabolic complications:
•• Hyperglycemia.
•• Dyselectrolytemia
Deficiency of micronutrients:
•• Vitamins
•• Minerals
Refeeding syndrome
Hepatic dysfunction
Box 4: Patients at risk of refeeding syndrome.

Body mass index (BMI) <16 kg/m2
•• Inadequate intake >10 days
•• Low potassium, phosphorus, and magnesium levels before refeeding
•• Chronic alcoholics
•• Severe chronic malnutrition
•• Depleted patients with acute illness
The most important and feared complication of PN is bloodstream

infection, both bacterial and fungal.36 To prevent this, there should be a
single dedicated port for PN in double or triple lumen catheters.
Refeeding Syndrome
Refeeding syndrome occurs when malnourished patients are restarted
feeding. It is a serious condition that occurs due to rapid changes in
fluids and electrolytes. Clinical symptoms include symptoms of fluid
overload like peripheral edema, congestive heart failure, respiratory
failure, encephalopathy, and multiorgan dysfunction. The main electrolyte
imbalance includes hypophosphatemia, hypokalemia, hypomagnesemia,
and hypocalcemia. The patients who are at risk of refeeding syndrome are
mentioned in Box 4.
ADJUNCTIVE THERAPY
Omega 3 Fatty Acids
Various studies have reported conflicting results in relation to supple
mentation of omega 3 fatty acids and antioxidants to standard EN. Earlier
studies in patients with acute respiratory distress syndrome (ARDS), acute
kidney injury (AKI), and sepsis showed improvement in length of ICU stay,
duration of ventilation and improvement in mortality in patients receiving
these supplements,37-39 but later post hoc analysis of MetaPlus study40
demonstrated potential harm of adding these and other meta-analysis

reported no benefit.3 Therefore, these are not recommended presently on
routine basis.
Glutamine
Amino acid glutamine serves as a metabolic fuel for the rapidly proliferating
cells. The plasma glutamine levels are usually low in critically ill patients and
low levels are associated with poor outcomes.41-43 There have been conflicting
results of various trials about the use of glutamine in the past. In the present
day, enteral glutamine is recommended only in burn and trauma patients
and not in other critically ill patients.3 Supplemental glutamine reduces
infectious complications and mortality in burn patients.44 Glutamine has
also been found to be beneficial in trauma patients in reducing infections.
The recommended duration of glutamine supplementation is 5 days in
uncomplicated trauma and for 10–15 days in burns and complicated wound
healing.45 Parenteral glutamine is not recommended. The investigators of
recently conducted large trial, REDOX (REducing Deaths Due to OXidative
Stress) TRIAL46 reported higher mortality in severely ill patients with the
administration of combined enteral and parenteral glutamine in doses
higher than recommended.
Fiber/Immune Modulators/Micronutrients/Antioxidants
Fiber can be added to EN in patients with diarrhea. Immune modulators have
no proven efficacy so are not recommended. Micronutrients include trace
elements and vitamins in the diet. They are required for the metabolism of
carbohydrates, proteins, and lipids. These micronutrients should be provided
daily with PN as parenteral solutions lack these. Antioxidant micronutrients
include copper, zinc, selenium, vitamin E, and vitamin C. ASPEN 2016
guidelines recommend the addition of these antioxidants in safe dosages.1
Vitamin D Supplementation
Vitamin D supplementation is required in the patients with measured low
plasma levels of 25 hydroxy vitamin D levels (levels less than 12.5 ng/mL or
50 nmol/L. Various trials have shown poor outcome with higher incidence
of sepsis and mortality in patients with deficiency of vitamin D.47,48 Single
dose of vitamin D3 (500,000 IU) in the first week of ICU stay is sufficient
and can be repeated if required.
Phosphate Supplements
Hypophosphatemia is common in ICU patients. The incidence of moderate
to severe hypophosphatemia is approximately 30% in ICU patients.49
Improving phosphate levels improves the respiratory muscle effort and

helps in weaning.50
NUTRITION IN VARIOUS DISEASE CONDITIONS

Sepsis
Patients in sepsis require special attention. There are increased metabolic
needs in patients with sepsis and on the other hand, these patients may not
be able to tolerate enteral feeds due to ileus and gastrointestinal intolerance.
This may lead to malnutrition in septic patients and if not provided, adequate
amount of nutrition can lead to reduced survival.51 Hypocaloric or trophic
feeding can be started in such patients but if they are unable to tolerate
even after 3 days, PN can be added in septic patients. However, in septic
shock patients, EN is contraindicated. There is already decreased splanchnic
perfusion in shock patients and there are chances of bowel ischemia or gut
necrosis with EN. It should only be started after resuscitation is complete.
Trauma
Trauma patients are usually optimally nourished on admission but may
become malnourished during critical illness. Studies indicate that an early
EN in this group of patients is associated with decreased mortality and
hence should be encouraged.52 Moreover, these patients have huge protein
losses and protein intake should be kept high around 1.5–2.0 g/kg/day.
Pulmonary Failure
There are no special nutritional requirements for patients with respiratory
failure. Earlier studies indicated some benefit with high fat and low
carbohydrate EN in these patients. High fat and low carbohydrate were
suggested in order to decrease the CO2 production and alter the respiratory
quotient, but these findings were refuted in later larger studies and therefore
should not be used.1 Overfeeding needs to be avoided in patients who are
prone to high CO2 production. Rapid infusions of intravenous fat emulsions
also should not be administered in these patients. Fluid-restricted
concentrated EN should be used in patients with volume overload.1
Renal Failure
In patients with acute kidney injury/renal failure, standard diet with proteins
(1.2–2 g/kg/day actual body weight) and energy (25–30 kcal/kg/day) should
be provided. The formulations may be altered if there are significant changes
in electrolytes, e.g. diet low in potassium and phosphate can be prescribed,
if hyperkalemia or hyperphosphatemia exists.53 However, in patients
undergoing frequent hemodialysis or continuous renal replacement therapy

(CRRT), high protein diet is recommended, as there are significant protein
losses.54
Hepatic Failure
Malnourishment is common in patients with chronic liver disease or
cirrhosis. Earlier, protein restriction was advocated in such patients to
reduce the risk of hepatic encephalopathy but studies have proven that
low protein diet can further worsen the nutritional status in such patients.55
Standard formulations with standard protein contents should be provided.
In patients with volume overload and ascites, dry body weight should be
considered instead of actual body weight. PN should be avoided in such
patients as it may worsen the liver functions.56 There is no role of branched-
chain amino acids in patients with hepatic encephalopathy who are already
on treatment.
Acute Pancreatitis
Early EN is recommended in patients with acute pancreatitis. Initially EN is
started as trophic feed and then increased to goal levels in 24–48 hours of
admission. Early EN has proven benefit in terms of reduced infection, organ
failure, ICU length of stay, and systemic inflammatory response syndrome
(SIRS) than delayed EN in these patients.57 PN should be avoided. Large
body of evidence indicates decreased length of stay, reduced infection, and
improved mortality with EN as compared to PN.58 There is no difference in
the outcome, if either gastric or jejunal route of feeding is used.
MONITORING NUTRITION
Like any other monitoring in ICU, monitoring for nutrition therapy is also
required. Inappropriate nutrition, which can be either underfeeding or
overfeeding can have dire consequences. This becomes more important
in chronically ill critical patients.59 Monitoring includes clinical monitoring
and monitoring of laboratory values (Box 5).
Glucose and Electrolytes Monitoring

Both hypoglycemia and hyperglycemia are associated with high mortality
in critically ill patients.60 The blood glucose levels in the range of 110–150
mg/dL are associated with good outcomes.61,62 Insulin therapy should be
started when blood glucose levels exceed 180 mg/dL. Electrolytes including
potassium, magnesium, and phosphates should be measured daily in the
first week of the nutrition.
Box 5: Monitoring the nutritional therapy.

Clinical monitoring:
•• Abdominal examination for distension, presence of stools, and nature of
gastrointestinal (GI) contents
•• Gastric residual volume
•• Intra-abdominal pressure
•• Detection of dysphagia postextubation
•• Delivery of nutrients—in terms of volume, energy, and proteins
Monitoring of laboratory values:
•• Blood glucose and insulin requirements
•• Concentration of electrolytes like sodium, potassium, magnesium, and chloride
•• Phosphate levels
•• Liver function tests
•• Triglycerides
•• Urea
•• Albumin levels
•• Micronutrients—vitamins, copper, selenium, and zinc levels
CONCLUSION
Providing adequate nutrition to critically ill patients is challenging. Critical
illness poses a major catabolic stress and timely, adequate nutrition therapy
is required to limit this stress and affect the outcome. Various available
guidelines help us to evaluate and prescribe nutritional components but
nutritional therapy needs to be individualized depending on the phase of
illness.
KEY POINTS
• Nutritional therapy moderates and restores physiological immune response
to critical illness.
• The requirements of a critically ill patient differ according to the severity
of illness and physiological stress.
• Assessment of nutrition is difficult in ICU and general clinical assessment
is recommended to assess malnutrition.
• Any patient staying in ICU for more than 48 hours is considered to be at
risk of malnutrition.
• The most preferred way of nutrition is early (within 48 hours of ICU stay)
enteral nutrition.
• The best method to measure resting energy expenditure is indirect
calorimetry.
• Approximately 70% of the estimated energy requirements should be
provided in the early phase.
• Both underfeeding and overfeeding can have dire consequences in
critically ill patients.
• Like any other monitoring in ICU, monitoring for nutrition therapy is also
required.
APPENDIX 1: NUTRIC SCORE

Variable Range Points
Age <50 0
50–<75 1
≥75 2
APACHE II <15 0
15–<20 1
20–28 2
≥28 3
SOFA <6 0
6–<10 1
≥10 2
Number of comorbidities 0–1 0
≥2 1
Days from hospital to ICU 0–<1 0
admission
≥1 1
(APACHE: acute physiology and chronic health evaluation; ICU: intensive care unit;
NUTRIC: nutrition risk in the critically ill; SOFA: sequential organ failure assessment)
Sum of points Category Explanation

5–9 High score Associated with worse clinical outcome
(mortality and ventilation)
0–4 Low score The patients have a low malnutrition risk
APPENDIX 2: COMPARISON OF VARIOUS

PARENTERAL FORMULATIONS AVAILABLE
Nutriflex Nutriflex Nutriflex
Smof- omega Smof- omega Smof- omega
Kabiven plus Kabiven plus Kabiven plus
Volume 986 mL 1,000 mL 1,477 mL 1,250 mL 1,970 mL 1,875 mL
Lipid type LCT/ LCT/ LCT/ LCT/ LCT/ LCT/
MCT/ MCT/ MCT/ MCT/ MCT/ MCT/
olive oil/ omega olive oil/ omega olive oil/ omega
fish oil 3 fatty fish oil 3 fatty fish oil 3 fatty
trigly- trigly- trigly-
cerides cerides cerides
Lipid gene- 4th 2nd gene- 4th gene- 2nd gene- 4th gene- 2nd gene-
ration generation ration ration ration ration
ration
Lipids (g) 38 40 56 50 75 75
Amino 50 38 75 48 100 72
acids (g)
Taurine Yes No Yes No Yes No
content
Carbo- 125 120 187 150 250 225
hydrates
Nitrogen 8 5.4 12 6.8 16.0 10.2
Energy 1,100 1,010 1,600 1,265 2,200 1,900
(kcal)
Nonprotein 900 860 1,300 1,075 1,700 1,615
energy
Osmolarity 1,500 1,215 1,500 1,215 1,500 1,215
(mosm/L)
Glucose to 57:43 57:43 57:43
lipid ratio
EFA con- 13 24 19 30 25 45
tent in g
NPE: N 113:1 158:1 108:1 158:1 106:1 158:1
ratio
Organic Yes No Yes No Yes No
glycero-
phosphate
better Ca
compati-
bility
Omega 6: 2.5:1 4:1 2.5:1 4:1 2.5:1 4:1
Omega 3
ratio
(LCT: long chain triglyceride; MCT: medium chain triglyceride; EFA: essential fatty
acid; NPE: non-protein energy; Ca: calcium)
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Smartphones in Anesthesia: Game Changers or Mere Distractions? 133
CHAPTER
9 Smartphones in Anesthesia:
Game Changers or Mere
Distractions?
Ranjana Khetarpal, JP Attri
INTRODUCTION
World is growing at an astonishing speed, thanks to the technology. Faster
internet connections at lower cost, launching of android phones and
I-phones and popularity of social networking sites like Facebook, Twitter,
and Instagram have made communication among people very convenient.
With so many medical applications introduced in smartphones, they have
become part and parcel of the lives of medical and paramedical people.
Rapid evolution of networks and devices and the widespread adoption
of the internet have changed the way people work. Smartphones have made
the greatest impact on everyday life. We can now communicate, collaborate
and collate information, and share expertise better. Nowadays, these devices
come armed with advanced computing capabilities along with the global
positioning systems (GPS) and high-definition cameras. The above features
of mobile phone allow the medical fraternity to use it to its full potential in
real-time patient monitoring, data collection, and provide medical services
to distant locations in the form of telemedicine.1
A physician today is bound to mobile phones in such a way that it has
become an integral part of his life. Numerous medical applications that
facilitate physician-patient communication are now available on Apple
and Android phones. The extensive adoption and use of mobile devices,
even in developing countries with resource constraints, is very promising.
Vital signs can be monitored from anywhere and at a very low cost. They
are being used for a variety of purposes such as personal and professional
scheduling, accessing drug related and other medical information as well as
e-mails. Mobile phones are carried by surgeons to the operation theaters for
the purpose of taking photographs, recording surgeries, and even play the
music. Additionally, immediate transmission of information is possible due
to these powerful devices. Several major smartphone platforms are available.
Specific tasks can be performed by mobile owner by using compact software
programs called applications. A study conducted in 20152 outlined that there
were more than 100,000 medical health and fitness applications available,
which further rose to around 325,000 on Google play store only and the
number is expected to grow by 16% within the next year as per Blog by
Lastovetska on January 24, 2019 (https://mlsdev.com/blog/healthcare-
mobile-app-development).
MOBILE INFORMATION TECHNOLOGY

APPLICATIONS IN HOSPITAL SCENARIO
Mobile information technology has become an indispensable part of
medical healthcare. It helps in faster access to medical information, recent
advances, and communication among healthcare workers and patients.
In emergency scenarios, several training applications for cardio
pulmonary resuscitation (CPR) and resuscitation algorithms downloaded
on smartphone can enhance perfor mance.3,4 The use of these phone
accelerometers has significantly refined the technique in various simulated
cardiac arrest scenarios.
A mobile phone flashlight providing an alternate light resource in case
of sudden unexpected failure of laryngoscope’s light bulb during an elective
case has been reported.5 The wide angle of the flashlight facilitated the
laryngeal view and allowed easy tracheal intubation.
Mobile technology also helps to reduce costs by enabling the provision
of healthcare to patients by allowing easy access to medical records and
laboratory test reports. A special mention is due here about tracking of the
location of patients with Alzheimer disease or dementia made possible
by the “I Wander app” for Android devices using GPS function. Not only
mobile apps, but social media platforms also play a pivotal role in helping
patients with chronic diseases such as diabetes to cope better. Discussion
platforms and support groups are formed by patients suffering from various
diseases wherein they discuss their management strategies and personal
experiences. Smartphones attached to cardiac monitor can function as
portable electrocardiography (ECG) systems for high risk cardiac patients.
Cardiac rhythm data can then be transmitted to the treating physician. An
application is available, which can convert I-phone into a device, which
can be used for monitoring vital signs including pulse oximetry. Now we
have smart automated external defibrillators (AEDs) where AED pads are
attached to the backside of smartphones. Once these AEDs are attached
to the victim, after removing them from phone, emergency team gets
the information about site via GPS and reaches there for resuscitation. It
prompts the responders like a traditional AED to carry out CPR. Recently,
there are reports of mobile phones being used as video laryngoscope to
guide and record intubations.6 Other important apps include TIVA (total
intravenous anesthesia) calculation, smart magnetic resonance imaging
(MRI), vein finder, simulation techniques, to teach various procedures like
ultrasound guided blocks, CPR, etc. in addition to access to various books
and journals.
4G network and the iPad have granted an easy access to the

anesthesiologists to access various journals and e-books available on internet
while at work. Numerous literature search application like Pub search are
available, which act as channels to access medical literature from PubMed/
Medline, the world’s largest library7 with a resource consisting of more than
7 million books in various forms such as journals, technical reports, and
manuscripts on medicine and related sciences, microfilms, photographs, etc.
With the help of interactive blogs, visitors can now leave comments
and even message. Examples are: the Indian Anesthetist Forum, Anesthesia
Today, ICU, etc.; power point presentations available on slide world are
among other invaluable resources.
The mobile devices are being increasingly used for medical imaging
purposes, challenging several traditional imaging techniques.8 Mobile
health (mHealth) imaging has improved image quality at reduced costs.
Visualization and navigation are available to orthopedists with the help of
smartphone applications. Arthroscopes are connected to smartphone9 to see
live videos for various procedures. Simulated surgeries can be performed
using apps providing precious opportunities for training and preoperative
planning. The games in smartphones can help in calming irritable children
preoperatively by keeping them engaged.
Availability of these facilities routinely promotes the practice of evidence-
based medicine. Disease diagnostic applications available on smartphones
allow retrieval of the diagnosis and treatment information. Ophthalmologists
can perform visual acuity tests using smartphone application. Several
medical calculator applications based on smartphone are also available.10
For obstetricians, AirStrip OB is a specialized app, which allows labor
and fetal monitoring and also allows access to electronic medical records
(EMRs). Smartphone application is very beneficial for training and
Continuing Medical Education (CME) in obstetrics.
Smartphone app (DelApp-ICU) has shown promise for objectively
detecting inattention and delirium in ICU patients, assess delirium severity
and allow longitudinal monitoring of deficits.11 A smartphone based mobile
telehealth system with the name of Borboleta was developed in Brazil for
home healthcare visits by nurses in lesser-attended areas.12 mHealth is a tool
of eHealth which delivers healthcare services with the help of mobile devices.
Many medical devices like glucometer and thermometer use the Bluetooth
technology for short distance wireless transmission of data.10 These devices
also make computing possible. Furthermore, entering data with respect to
patient’s demographic data can get you all the drug information, dosages,
ventilator settings, etc. in no time. With the availability of WhatsApp, clinical
photographs X-rays images can be shared for immediate consultation.
Similarly, a variety of social networking sites are available for use,
among them the most popular are twitter, YouTube, and Facebook. While
Facebook and Twitter are used to obtain updates and share clinical research
in use, they also connect individuals with mutual interest in medical field.10
Specifically for anesthetist there is a server network by the name of Gannet
(Global Anesthesiology Server Network) which has been functioning since
1994. Podcasts and YouTube serve as channels to discuss clinical problems,
share educational videos that can be accessed by all and put to use for just
in time training.13,14
But, using social media is like walking on a tight rope which is highlighted
brilliantly in a study conducted in Turkey which reported that 41% of
anesthesia providers had witnessed their colleagues’ use of smartphone
which could have led to adverse medical incidents.15 Social media also poses
a risk to the privacy of users and patients whose photos could have been
published without their consent. There is also a possibility of unnecessary
arguments between the users which may bring disrepute to the whole
fraternity. Thus, there is strong need to outline measures to ensure their
judicious use. Also, every social media site is not very authenticated; hence,
it should not be trusted blindly.16 With the use of automated telephony
immediate feedback and corrective actions may be taken immediately.17
DISEASE PREVENTION AND HEALTH PROMOTION

Mobile phone apps have led to some promising changes in the lifestyle
which helps in improving patient’s health behavior. Plethora of apps has
emerged in an unprecedented way to promote healthy lifestyle among
the smartphone users.18-20 Many apps are available like pill phone which
helps the patient to set reminder so that they do not miss their dosage of
pill and remain compliant to the treatment.21 Some apps can be used as
peripheral sensors to rehabilitate the patient with gait deformity.22 Mobile
accessories have also been used continuously to measure and record the
central body temperature,23 easy detection of malarial parasites, sickle red
cells and Mycobacterium tuberculosis (M. tuberculosis) in blood and sputum
smears,24 and to monitor CD4 count in human immunodeficiency virus
(HIV) affected patients.25 Thus, mobile technology provides a cost-effective
way to improve diagnostic facilities in remote areas using telemedicine.
SMARTPHONE AS A COST-EFFECTIVE VENTILATOR

In most of the developing countries many lives are lost every year due to lack
of ventilators.26 It is estimated that more than 2 million lives are lost due to
dearth of ventilators as reported by World Health Organization (WHO) India
in 2012. The major reason behind this is the high cost of equipment, lack
of trained individuals, and inadequate resources.27 The above situation calls
for a low cost and low maintenance device to provide the basic ventilatory
support to the needy. One such device has been created at All India Institute
of Medical Sciences (AIIMS), India, where a smartphone was used as a
ventilator, which works on room air and costs only around Rs. 35,000/-.
CONCERNS ARISING OUT OF MOBILE USE IN HOSPITALS

Spread of Nosocomial Infections
Nosocomial infections always remain a dreaded risk in the medical centers.
Mobile phones are seldom clean as there are no fixed guidelines on how to
properly sterilize them. Touching them during patients’ examination turns
them into vectors for transmission of diseases.28-30 The hygiene in the hospital
operating room (OR) is supposed to be sacrosanct. Equal requirements of
hygiene are applicable to the OR personnel and equipment.
In a study of hand disinfections, 40 anesthesiologists were asked to
make a short call using their personal mobile phone while at work in OR.31
High rates of bacterial contamination of anesthesiologists’ hands (38/40)
were found after the use of cell phones. Rates of contamination of the
anesthesiologists’ hands were somewhat lower (33/40) when the test was
repeated after use of the fixed phones. The study concluded that there
may be serious hygiene consequences associated with the use of mobile
phones. Less serious hygiene consequences associated with the use of fixed
phones was explained by the fact that fixed phones are not used close to
patients in OR unlike mobile phones. Recommendations are not available
for cleaning mobile phones as per the hospital standards. Use of cleaning
agents is explicitly forbidden by the cell phones manufacturers. So, the risk-
benefit ratio of using telephones, especially mobile phones in ICU must be
carefully weighed. Several authors have confirmed the hazard of a high level
of contamination associated with the use of mobile devices in healthcare
settings.32-34 Ogg expressed concern over cellular phone use in the OR and
enunciated that cross contamination of the practitioner’s hand was possible
by devices contaminated by bacteria.35 Bacteria carrying potentials of cell
phones was proven in a study conducted in Ireland that showed 70% of cell
phones harbored infection causing bacteria. Shekhar Pal et al. also reported
highest contamination rates among hospital staff and doctors with highly
pathogenic bacteria.36 All the above studies point toward an alarming rise in
the spread of nosocomial infections which needs to be urgently addressed
and measures need to be put into action.
Distractions
Distractions make learning difficult in ICUs. The term “distracted doctoring”
is the term specifically used here to address this problem wherein the
medical professional is focused more on the screen and not on the
patient.37,38 Anesthesiologists can multitask while maintaining awareness
of their surroundings but not without risks. During multitasking, the
hippocampus which is the part of the brain involved in the processing and
sharing information is not engaged.39 Making phone calls while performing
tasks related to work result in distraction and prolonged reaction time.

Vigilance is defined as “a state of readiness to detect and respond to small
changes occurring at random intervals in the environment”.40,41 Vigilance
is a key determinant of human performance at work especially for high
performance/high risk services including aviation, defense and anesthesia,
etc. Philip Stanhope, 4th Earl of Chesterfield advised his son “there is time
enough for everything in the course of the day, if you do but one thing at
once, but there is not time enough in a year, if you will do two things at a
time”.42 Multitasking usually leads to underperformance if many things are
attempted at the same time and only 2–3% of people can actually multitask.
Mobile phones are considered as a source of distractions for everyone in
the OR including the operating surgeons, anesthetists, and the other staff.
It is similar to the aviation industry wherein “sterile cockpit rules” have
been enforced to reduce accidents that happen during the conversations
and nonflying related tasks done by the pilots during take-off or landing.9
It is also seen that distractions caused by the use of mobile phone can
compromise the performance not only of the individual but the entire
team also leading to avoidable errors. In healthcare, any small mistake can
prove fatal. It is a common practice to watch residents and even senior
anesthesiologists sitting by the side of operation table, busy looking at the
screens of their mobile phones. More often than not, they are actually
texting their friends, ordering products on Amazon, posting status, or,
uploading pictures of their visit abroad on Facebook or Twitter. Chances
of someone looking at some vital health data or patient information are
very bleak. In one 2011 Texas incident, an anesthesiologist was accused of
texting and emailing when she was supposed to be monitoring a patient.
She failed to notice the dropping oxygen levels for 20 minutes and lost the
patient. She was sued by the family of that patient. Several other medical
errors have been reported. One such case was when a resident failed to stop
anticoagulant therapy in a postoperative patient due to distraction by text
message on smartphone.38 Each interception to medical care workflow leads
to 12.1% increase in procedural failures and a 12.7% increase in clinical
error at an Australian hospital.43 Distractions by cell phones are common
among perfusionists with one study reporting cell phone use in 55.6%
of 439 perfusionists during cardiopulmonary bypass and a consequent
negative impact on performance of 7.3%.44 Cain and McBride established
that one of the constant sources of disruptions was accessing social media
with smartphone.45,46 Ringtone from mobile at crucial moments especially
while performing crucial procedures such as laryngoscopy, endotracheal
intubation or during surgery may cause distraction.
Peter Papadakos, a professor of anesthesiology at the University of
Rochester, says “if you are staring at a phone, you are not staring at the
monitors”.47 In 2012, Emergency Care Research Institute (ECRI), a nonprofit

institution listed cell phone distraction among top 10 risks to patient safety.48
It is like texting while driving and accidents can happen anytime. Keeping
phones in “silent mode” is only going to address the noise level but does
nothing about the major issues of distraction and infection? Many people
talk about using medical Apps in ORs but how to monitor the activities of
those involved with cell phones and for how long? Pros and cons need to be
considered before we can develop definite guidelines on how to get benefits
and avoid distractions at the same time!
SMARTPHONES AND THE MEDICAL EQUIPMENT

Plenty of concerns and speculations have been raised regarding the electro
magnetic radiation emanating from smartphones interfering with the
working of crucial equipment in operating theater (OT) and ICU. Therefore,
it is advisable to keep them at a safe distance from medical equipment.
Noise from ringing of mobile phones and interference related to disturbance
of signal seen on the cardiac monitor are major concerns in the ICU.49
Effects have been found on both, the permanent and temporary pacemakers
leading to misinterpretations. Mobile phones interfere with pacemaker
only up to a distance of 10 cm from the equipment. Irnich and Tobisch
proposed “1 m rule”, which restricts the use of mobile phones to >1 m from
the equipment.45 In countries, where phones operate predominantly in the
safer 1,800 MHz band there is nonsignificant EMI and effect on medical
equipment is seen only if closer.46 Improved newer equipment are less
sensitive to interference.50-52
Wigmore drafted three categories of mobile phone usage policy to
improve communication and services, optimize work efficiency, and
safeguard patient safety.52
Category 1: Nonclinical/low risk patient areas (e.g. daycare rooms, reception,
waiting rooms, and corridors). Unrestricted access to mobile phones may
be permitted.
Category 2: Clinical patient areas (e.g. in patient areas and clinical
departments). Restricted access to mobile phones may be permitted,
ensuring to safeguard patient dignity and confidentiality without interfering
with patient care.
Category 3: Safety critical patient areas (e.g. OTs, ICUs, CCUs, HDUs, etc.).
No access to mobile phones to patients and visitors. Access allowed only to
clinical staff with extreme caution, if within 1 m of sensitive medical devices
associated with life support.
GUIDELINES REGARDING SAFE

USE OF SMARTPHONES41,53
• In safety critical patient areas (category 3) mobile phones should be
permitted only for communications concerning patient management
and must always be used with extreme caution and more than 1 m away
from life support medical devices.
• It should be mandatory for the staff to switch off their personal mobile
phones in category 2 and category 3 areas.
• Patients should be advised not to use mobiles phones within 1 m of
sensitive equipment such as monitors.
• Smartphones should be collected in sterile bags when entering patient
care areas to reduce contamination risk.
• Use gloves when making physical contact with patients. Gloves should
be changed after using a smart device in patient care areas.
• Hand sanitizers should be used at regular intervals, especially before
and after contact with the patient. Sanitizing wipes can be used to clean
mobile devices regularly.
• “No mobile/No smartphone” zones should be created in ICU, OT, etc.
• Ring tones and alert tones used by healthcare professionals must be
regulated.
• Access to social networking sites must be blocked. Cellular/smartphone
permitted and restricted zones must be established.
• Personal phones and other devices may be allowed only during breaks
at specific hot spots created for the purpose.
• Shooting photos and videos while at work should not be permitted
without obtaining prior permission. It must be mandatory for everyone
to adhere to organizational ethics.
• Posting work related information on social network should be governed
by clear policies.
• Employees must be encouraged to frequently change passwords.
Websites with low security must be blocked.
ETHICAL AND LEGAL ISSUES WITH SMARTPHONE USE

Mobile phones with camera facility pose a considerable risk to medical
confidentiality, intrude into patient’s confidentiality, private life as well as
possible contravene data protection Act 1998. Additionally, there are issues
of nuisance to staff and other patients.
SUMMARY AND CONCLUSIONS

Smartphones are increasingly being used by healthcare professionals at all
work areas. Their use has revolutionized communication and collaboration
among different healthcare professionals. But the question remains; should

smartphones be allowed in operation theaters and critical care areas? Let
us talk about operation theaters first where residents are actively involved
in continuous monitoring of patients under anesthesia, of course under
the supervision of seniors. We, as faculty, have witnessed our residents
engrossed deeply with their phones after putting the patient on ventilator
attached to workstation. It is like using your mobile phone while driving
thus inviting accidents. One approach would be to put jammers thereby
not allowing anyone to use his or phone. But instead of this extreme
approach we can have a restrictive approach. A dedicated area adjoining
the operation theaters can be chosen with the Wi-Fi and computer facility
which should allow limited access to authorized people with a password for
accessing important information about investigations, etc. about patients
and for academic activities. Access to social media and marketing should
be denied.
Considering issues of distraction and infection, time has now come
to have clear and strict guidelines about smartphones usage else we are
heading toward disaster. They may be allowed with restrictions in places
like doctor’s duty room in ICU but with limited access to social media sites
or entertainment. Smartphones impair higher functions and adversely affect
cognitive performance. Noise, interruptions, and emotional arousal can
strain limited human attention span.38 Cameras on mobile phones must
not be in a patient care area to maintain patient confidentiality.
Risk-stratified policy in the form of written clear-cut instructions to all
medical and paramedical staff with provision for strict disciplinary action
in case of any lapses should be formulated and enforced. Selected access to
encrypted information can be provided so that the full attention is toward
the patients and acts of omission and commission can be minimized. This
will also save medical fraternity from unnecessary legal implications. On the
flip side, smartphones have led to better mHealth and mobile telemedicine
services through patients’ oriented applications.
We can conclude that the smartphones and mobile devices have
quintessential to the physician’s life and have remarkably improved the
medical care. Both opportunities as well as challenges present with their
use. They carry the potential to compromise security and privacy of the
patients, are source of distraction and infection, and can compromise
the quality and efficiency of patient care. A sensible and evidence-based
balanced policy toward mobile phone usage in our clinical practice needs to
be adapted to rationalize their use with safety. These technological marvels
can impact the anesthetist’s performance both positively and negatively and
should be utilized with great diligence.
KEY POINTS
• Smartphones have become an integral part of our lives and have touched
the healthcare system in a big way. Rapid evolution of networks and
various apps contribute significantly toward patients care in the form of
dose calculation, monitoring of patients from remote area, various training
programs like CPR.
• Smartphones are also double-edged swords for medical professionals.
In addition to offering various benefits, they are source of nosocomial
infections, distraction, interfere with medical equipment functioning, and
also pose threat to patient’s privacy.
• Risk stratified and clear-cut policies regarding their restricted and
rationalized use in operation theaters and critical care areas need to
be framed and implemented strictly in the best interest of patient care.
Setting up of high security and password protected networks with warning
of disciplinary actions in case of lapses is the need of hour.
• Usage of smartphone, if used in ICUs, should be at a distance of 1 m
from all life-saving equipment.
• Make the devices your strength and not a hindrance or obstacle to patient
care.
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Health Hazards for an Anesthesiologist: A Myth or Reality? 145
CHAPTER
10 Health Hazards for an

Anesthesiologist: A Myth or
Reality?
Susheela Taxak, Reeta Singh
INTRODUCTION
“Qualities you need to get through medical school and residency: Discipline.
Patience. Perseverance. A willingness to forego sleep. Ability to weather crisis
of faith and self-confidence. Accept exhaustion as a fact of life. Addiction to
caffeine is a definite plus. Unfailing optimism that the end is in sight.”
—Khaled Hosseini
Khaled Hosseini, famous novelist and formerly a physician, mused about a
doctor’s life in this above-mentioned quote. Any sane person can point out
all the wrongs in his description of work pattern of doctors. Anesthesiologists
are no different breed of physicians; they endure strenuous lifestyle, work
inhuman hours, and are at massive amount of stress to be the best at their
work, as patients’ lives are in their hands. Anesthesiology is a pioneering
specialty, which has done the most among various medical specialties to
reduce the risk to patients under its care. Parallels are drawn in anesthesia
with aviation industry to ensure safety and minimize risk. Anesthesia
workstations, anesthesia plan, optimization of medical condition and
preparation of patient, equipment, drugs, and team are all meticulously
verified as standard practice before the start of every anesthesia procedure,
just as in aviation before take-off. However, this most safety-oriented
specialty toward patients is among the top medical specialty in terms of
occupational health hazard to its consultants. Is this a myth or a reality?
The scope of anesthesiology has widened from the operation theater
(OT) to the intensive care unit (ICU), labor room, emergency department,
trauma or disaster situations, resuscitation rooms, pain clinics, outpatient
consultations, and procedures to remote locations, wherever sedation or
anesthesia care may be required, to transfer of unstable patients between
departments/hospitals and the list is unending. The anesthesiologist is the
most important person in any difficult situation in the hospital, toward
whom everyone looks when in trouble. Yet there is not much knowledge
and recognition to what the anesthesiologist actually does by the clientele
and colleagues. Literature is full of articles and there is much focus on the
risk to the anesthetic receiver, the patient, but, the health hazards that the
anesthesiologist, who delivers the anesthetics’ faces are scarcely published.
As we delve historically into the lives of the great pioneers of anesthesia,
we realize the psychological stresses suffered by the early anesthesiologists.
Horace Wells suffered from severe depression, addiction, and committed
suicide. Morton could not complete his medical degree despite his fame
as the person who conquered pain. Addictions, depression, suicides, and
crippling backaches were known. Fires and explosions inside the operating
room caused by inhaled agents were the biggest hazard early in the 20th
century. Later, the long-term effects of chronic inhalation of anesthetic
gases and contamination of the operating suites, and recovery rooms
were highlighted. After the advent of scavenging systems and gas sample
analyzers, this was brought down, but there emerged the risk of blood borne
infections and rising drug abuse seen in anesthesiologists. Presently, many
occupational risk factors are being studied, like drug abuse, work-related
stress, and burnout. The death of Chicago anesthetist Costain, in 1922, who
had anesthetized 30,000 patients in his lifetime, was announced with the
headline “Noted Anesthetist Dies a Martyr to His Skill” when it became
known that it was the complications arising from anesthesia exposure that
had led to his demise.1
An anesthesiologist’s life is challenged with unending work shifts,
frequent calls, stress ridden environment, and pressure to accommodate
more cases so as to contribute more to hospital productivity, exposing him
to multiple health safety and performance hazards. The present routine of
anesthesiologists exposes them to multiple ergonomic, chemical, biological,
and psychological risks. These factors affect the quality of life of not just
the worker, but of their families as well. This is why anesthesiology is
believed to offer a higher occupational health hazard as compared to other
healthcare branches. Even in today’s time our students feel they need to
put up and shut up, and that they need to internalize all their stress if they
need to successfully complete the anesthesia degree. Students end up using
unhealthy ways of adapting, which become lifelong hard to deal with habits.
The World Health Organization (WHO) constitution defined health
as a state of complete physical, mental, and social well-being and not
merely absence of any disease or infirmity. Healthcare sector is next only
to manufacturing sector in the number of occupational hazards sustained
by the workers, according to statistics provided by the US Bureau of Labor,
anesthesiologist have been reported to be victims of various occupational
health hazards over the years, a few of which are listed below:
• Physical hazards:
▪▪ Waste gas exposure
▪▪ Radiation exposure
▪▪ Allergies
▪▪ Infection inoculation
▪▪ Poor pregnancy outcomes
• Mental hazards:
▪▪ Stress and burnout
▪▪ Substance abuse
▪▪ Ambience-related stress
• Other hazards:
▪▪ Impairment and disability
▪▪ Malpractice claims
▪▪ Violence
▪▪ Fires and accidents.
PHYSICAL HAZARDS
Waste Gas Exposure
Volatile anesthetic gases like nitrous oxide, halothane, isoflurane, desflurane,
sevoflurane, etc. in the working environment of anesthesiologist have
been known to induce carcinogenesis, mutagenesis, and hepatotoxicity
in various mice, animal and human experiments. Their subchronic and
chronic exposures include effects on central nervous system (headaches,
dizziness, fatigue, and memory lapses); effects on liver (halothane hepatitis,
raised liver enzymes, and massive cell necrosis); and effects at genetic
level (chromatid exchanges, chromosomal aberrations, and micronucleate
derangements). Some studies have also found increased incidence of
lymphoma, leukemia, and other malignancies in the exposed populations
compared to control populations. The National Institute for Occupational
Safety and Health (NIOSH) recommendations, 1977, remain the standard
set of guidelines to reduce the exposure of waste anesthetic gases to the
healthcare worker by setting up a recommended exposure limit (REL) for
anesthetic gases. These guidelines have been modified and adapted to form
workspace recommendations in order to reduce the chance of poor health
outcome in anesthesia workers as discussed historically in numerous texts
and studies conducted all over the world that claimed harmful effects of
these gases. However, a recent study of year 2001 found that there was
hardly any evidence of health risks associated with occupational exposure
to volatile anesthetics, but neither did they find evidence that these gases
were harmless, leaving us perplexed. They observed that almost all the
studies that claimed potential health hazards of these gases lacked modern
environmental regulations and scavenging equipment in their workplace.
No animal or human studies have provided any conclusive evidence of
direct severe organ toxicity of halogenated anesthetics, if the exposure
was in low concentrations and over a chronic period of time. Use of air
circulation mechanism in the operating theaters, suction and scavenging

systems, low flow rates, and use of cuffed endotracheal tubes have turned
out to be effective measures in minimizing exposure to these gases to the
ideal standards.2
However, a 2018 study raised doubts over practicality of reaching these
ideal recommended standards. They studied a modern anesthesia recovery
room with scavenging system and ventilation protocols built according to
latest codes and guidelines. They found that the ambient level of sevoflurane
exceeded the ceiling set by NIOSH guidelines at all days they measured and
concluded that the workers were exposed to these harmful concentrations
of gases chronically, despite all efforts to build an ideal workplace.3 Efforts
are on in development of newer anesthetics that have almost negligible
harmful effects. Thus, these studies pose more questions to us than answers
to the questions. Are these gases harmful? Or, are these gases harmless? Are we
being overcautious? Should we be overcautious? The controversy remains.
Radiation Exposure
Anesthesiologists are required in radiology suites for sedation during
computed tomography (CT) scans, magnetic resonance imaging (MRI),
and positron emission tomography (PET) scans, in cardiac catheterization
laboratories, endovascular repair procedures, and in fluoroscopy rooms.
Involvement of anesthesiologists in interventional pain has exponentially
increased the exposure to pain specialists. The ionizing radiation affects
organs that are most susceptible like the gonads, followed by bone marrow,
thyroid, lungs, colon, eyes, and stomach. The International Commission on
Radiological Protection (ICRP) is an international committee that has set
the allowable annual occupational exposure at 20 mSv.4 National Council
of Radiation Protection and Measurement (NCRP) of United States gives
the safe annual occupational exposure limit up to 50 mSv per year.4 A
2014 study by Ari et al. studied the radiation exposure to anesthesiologist
during endovascular aortic aneurysm repair procedures and compared
it to interventional neuroradiology. They found that there was lower
total radiation dose emitted by the fluoroscopic equipment during the
endovascular aneurysm repair procedures, however, the radiation exposure
to anesthesiologist’s temple was found to be significantly greater during this
procedure as measured by the dosimeter placed on the anesthesiologist’s
forehead. The exposure never exceeded the safe ocular exposure limits.5
Thus, it becomes crucial to limit the duration of radiation exposure, increase
the distance from the source of radiation scatter, and utilize lead shields and
protective eyewear even if the said risk of radiation exposure is minimal.
The radiation scare to the anesthetist is thus a reality but the evolvement of
improved radiology and protective equipment, awareness, legislation about

the use of dosimeters have minimized the risks to the anesthesia workers.
Allergies
In the operation theaters, the surgical field as well as the anesthetic workplace
has plenty of potential allergens. Muscle relaxants like succinylcholine,
latex products, opioids, colloids, iodine containing compounds, radioactive
material, antibiotics have been on and off reported as source of allergies in
healthcare workers including the anesthesiologist. They are mainly exposed
to these irritants and allergens by inhalational or cutaneous exposure in
the operation theaters. Some people are genetically predisposed to these
allergies, also called atopy. Latex allergy is a widely recognized entity in
the hospitals. The effect of latex allergy can present with a delayed type IV
reaction mediated by T-cells like irritant contact dermatitis and even by
an anaphylactic shock mediated by immunoglobulin E (IgE). Correlation
has been found with a history of allergy to certain foods such as bananas,
avocado, and kiwi fruits. Every operation theater should run educational
activities to improve awareness and encourage hand-washing immediately
after contact with latex containing products to reduce the prevalence of
latex allergy.6 This dermatitis is often exacerbated in the operation theater
worker by use of strong soaps and compulsory frequent hand-washing
which further dries up the skin and makes it a vicious cycle of allergy.
Latex is present not only in gloves but also it is insidious in face masks,
ambu bags, tubing, drains, catheters, rubber stoppers of vials, dressings,
and equipment. Inhalational agents and powders in the gloves are known
to cause conjunctivitis, rhinitis, and bronchitis.7 Some individuals may even
develop cardiovascular compromise in the form of tachycardia, hypotension,
chest pains, and sometimes severe anaphylactic shock.8 Gastrointestinal
symptoms like severe crampy abdominal pains, chronic diarrhea due to
allergy to certain irritants in the OT can be misdiagnosed as infection, stress
related or sometimes inflammatory bowel disease.9 The need of the hour
is use of hypoallergenic products in the OT like powder free and latex-free
gloves, recognition of susceptible individual and use of personal protective
equipment, frequent housekeeping and vacuuming of anesthesia workplace,
use of milder variety of soaps, and increasing awareness of this important
occupational hazard among everyone.
Infections
Hepatitis B and C viruses along with the notorious human immunodeficiency
virus (HIV) have caused significant morbidity in healthcare workers,
including anesthesiologists. Exposure to airborne pathogenic agents like
tuberculosis and contact infections like methicillin-resistant Staphylococcus
aureus (MRSA) places the anesthesiologist at increased health hazards. For

anesthesiologist, the most likely source of an occupational exposure is self-
inoculation from resheathing of used needles, while inserting or suture
fixing the intravascular catheters or while injecting local/regional anesthesia
blocks.7 Awareness about universal work precautions, vaccinations, pre-
cautions in syringe and sharps handling, waste management protocols,
screening of blood, blood products, and tissues for viral markers have
substantially reduced the incidence of new infections.
Poor Pregnancy Outcomes

Females constitute a large proportion of anesthetic workforce. Various
pregnancy-related hazards have been documented over years like
spontaneous abortions, preterm deliveries, congenital malformations,
low birth weight babies, and many other perinatal complications. While
it is established that there is a positive correlation between exposure to
anesthetic gases and adverse pregnancy outcomes, but there are certain
limiting viewpoints that must be considered regarding these studies. Most
studies selected similar groups from the hospitals to compare the anesthesia
work group.10
MENTAL HAZARDS
Stress and Burnout
Stress is the nonspecific response of the body to adapt to any change
or demand or a pressure situation or a challenge. It involves physical,
psychological, and behavioral ramifications in response to a real or perceived
threat or trauma. Anesthesiologist face myriad varieties of stressors everyday;
sick patients [American Society of Anesthesiologists (ASA) status III and IV]
who approach for surgeries, patients with difficult airway, irregular working
hours, complex inter- and intra-departmental interactions, unhealthy food
and lifestyle, need for continuous upgradation of medical education and
skills with time, unanticipated clinical misadventures and associated
medico-legal consequences are some. Other studies resonates the same.
Personality of a person plays an important role in deciding who gets burnt
out and who survives. Neurotic individuals have been shown to tend to
get burnt out, whereas extravert and agreeable persons were protected
from it. Many studies have described burnout in anesthesiology, including
different workers profiles (nurses, residents, consultants, and directors). The
prevalence of burnout greatly varied across studies from 10% to 59%. Strained
working patterns, younger positions of consultants, anesthesiologists who
had children, were the factors most consistently associated with burnout. No
relationship was found between burnout and hospital characteristics, gender,

or marital status.11 A recent study suggested possible use of personality tests
and appraisals at selection centers on applicants for admission into stressful
medical specialties like anesthesiology.12
Substance Abuse
The American Association of Nurse Anesthesiologist (AANA) showed that 15
in 100 anesthesia workers, Certified Registered Nurse Anesthetists (CRNAs),
and anesthesiologists were addicted to substances. According to their
studies, the greatest at-risk population were younger male CRNAs. Drugs
that are commonly misused by the anesthesia provider are benzodiazepines,
opioids like fentanyl, barbiturates, dissociative drugs like ketamine and
inhalational agents. The most commonly misused drug was midazolam
followed by nitrous oxide, fentanyl, sufentanil, propofol, and ketamine.13
Changes in behavior like outbursts of anger, impaired job performance,
poor interpersonal interactions, mood swings, reduced or even exaggerated
libido are all signs of drug abuse. The coworkers are liable to bring to notice
a drug dependent anesthesia provider or they may be held responsible
for failure to report a malpractice. Substance abuse not only affects the
anesthetist but also the patient entrusted to his care, violates the sacred
patient-doctor relationship and is criminally unacceptable. “Do no harm/
primum nonnocere” becomes just an anecdote.
Ambience-related Stress
Beeps, alarms, and bells, screeching and clanking metal trolleys and
instruments, false alarm bells, along with low lighting, poor ventilation;
this is the composition of anesthesia workplace. “Alarm fatigue” is the new
reality. Frequent false alarm bells distract the clinician, exhaust his patience,
and instead of helping him, these hinder his care toward the patients.14 The
Food and Drug Administration (FDA) and Manufacturer and User Facility
Device Experience (MAUDE) showed 566 patients death reports due to
alarms caused by monitoring device between the years 2005 and 2010. The
need of the hour is to reduce the burden of noise pollution on patients
and doctors. Technology employing artificial intelligence to identify crisis
situation and reduce the number of false alarms is worth investing in. Short
delays between two alarms can reduce the number of ignored alarms.
Setting alarm volume, tone, pitch, and various other control parameters
can help the physician to identify important alarms from the unimportant
ones, to reduce his work stress.
OTHER HAZARDS
Impairment and Disability
Anesthesiologists are a vulnerable set of physicians wherein even the
slightest impairment, physical, psychological, intellectual, behavioral,
spiritual or social may affect their work and skills. In a sampled study, 50%
of all anesthesiologists suffered from low back ache and attributed this low
back pain subjectively to their clinical practice. This was associated with
absences from work or changes in work schedules due to sickness. The study
highlights a necessity to include ergonomic training programs and teaching
proper lifting and moving techniques in anesthesia training program to
prevent musculoskeletal injuries.15 An impaired anesthesiologist may be
difficult to spot as he may be competent in his everyday household chores
but may not be competent in execution of his duties as a perioperative
physician. The vice versa could be true as well. One of the most common
sources of disability is substance abuse disorder as discussed above. Other
causes may be psychiatric illnesses like depression, burnout, personality
disorders, which may manifest in the anesthesiologist. Hearing impairment
is also not uncommon in anesthesiologists. A study demonstrated that
almost 66% of anesthesiologists had abnormal audiograms especially at
higher frequency. Abnormal loudness perception, tinnitus, and difficulty
with sound localization are other problems affecting anesthesiologists. This
may affect their ability to listen to audio alerts and alarms in the OT and
ICU. Exposures to bright lights and visual impairments in anesthesiologist
have shown to cause impeded intubation skills and errors. Similarly, old
age may not be considered as disability, elderly anesthesiologist may find it
difficult to function in night shifts and for longer working hours. Cognitive
impairment due to age or any other cause like Alzheimer’s disease may
hamper their agility and quick thinking. In a 2013 survey, it was found that
among Canadian anesthesiologists, 22% were in the age group of 55–64
years, 7% in the age group 65–74 years, and 3% were older than 74 years.
They concluded that adverse patient events had an association with elderly
anesthesiologists, younger and middle aged anesthesiologists scored better
in this regard.16 In another study conducted in Ontario, Quebec, and British
Columbia, anesthesiologists older than 65 years had 50% more cases of
litigation.17 All impaired anesthesiologists should be given opportunity for
assessment of their problems and provided remediation and rehabilitation.
Malpractice Claims
Most doctors at some stage of their career have had the unpleasant experience
of being held liable by a patient who has suffered a major or minor adverse
outcome.18 The malpractice lawsuit sets back the anesthesiologist or any
physician not just financially but also impacts his/her professional and
personal reputation. As per a Medscape survey only in 2% of malpractice
cases, there has the verdict been given in favor of the plaintiff but win
or lose, the defendant anesthesiologist being sued loses a lot of valuable
time and can suffer immense loss of reputation. The survey showed that
anesthesiologists on an average spent about 40 hours preparing for trial
and up to 50 hours in court, for 1–3 years or even more, the changing
patterns of surgeries in favor of day case have led to more cases of lawsuits
on outpatient procedures, but the amounts of settlements and awards have
shown a downward pattern.
Violence
Critical care units and operation theaters are stressful places for not only the
patient and the doctor but also for the relatives of the patient. A 2003 survey
in ICUs of England and Wales interviewed nurses and doctors about their
unpleasant encounters with the patients and their relatives in the last 12
months and found that violent behavior was common place in these places.
They found that 65% of the doctors reported abuse by the patient and 38%
times it was physical abuse.19 Nurses fared a lot worse; 77% of the nurses
had faced some sort of physical abuse in last 12 months.20 In the operation
theater, there is another problem faced by the doctor; emergence delirium
in patients after general anesthesia, which is a common occurrence.21
Patients often wake up with violent behavior, thrash the anesthesiologist,
forcefully pull out wires, lines and catheters causing self-injury, risk falling
from the OT table and injuring themselves. Some may even extubate
themselves. These patients not only harm the operating room workers but
also themselves. Various factors have been identified in precipitation of this
delirium including use of benzodiazepines preoperatively, long duration
surgeries, breast surgery, and abdominal surgery.
Fire and Accidents

Operating rooms have an oxygen-enriched atmosphere, which may also
include nitrous oxide and is the reason behind most fires reported from
there. In a panel discussion at the ASA annual meeting in Dallas in
October 1999, entitled “Fire in the Operating Room! Still a problem,22 it was
highlighted that fire is often under reported in operating rooms and it was
estimated that only 1–10% operating suites fires are reported. FDA reports
and ECRI investigations (United States) figures show an annual incidence
of between 100 and 200 fires in the operating rooms. Serious patient harm
has been reported in 20% of these. Patient deaths have been reported rarely
and are secondary to airway fire.
CONCLUSION
The occupational health hazards in anesthesiologists are a reality but the
extent of exposure to these risks can be markedly reduced, if every hospital
and department administration focuses on quality in the practice of the
specialty and keeps risk analysis and risk mitigation at the forefront of
its activity planning and practice. Strict adherence to best practices and
availability of safety equipment and gear should be audited and enforced
in every area where anesthesiology and related subspecialties are practiced.
Implementation and follow-up of accreditation programs have provided
credible evidence that the process of accreditation improves the quality of
care provided by healthcare agencies and improves the clinical endpoints
and also indirectly improves the occupational health and safety of health
workers.23
A sharp reduction in the premiums of the professional liability and
insurance for anesthesiologists from the 80s to the present reflects how better
equipment, utilization of fail-safe back up devices and improved monitoring
of patient has improved the practice of anesthesia and made it safer.
Anesthesia related deaths which were 1 in 1,500 in 1973 and now reduced
to 1 in 200,000.24 Thus, the overall landscape for anesthesiology practice has
improved to a great extent both for the patient and the practitioner and the
main reason is improved training and education, recognizing that human
errors are possible, more opportunities and regulatory requirements for
practitioners to get qualified and trained, and healthy competition between
hospitals to engage insurance companies and clients and retain competent
staff.
Rules of operational excellence are important at all work places and it
is the duty of every anesthesiologist/team leader/supervisor/manager to
ensure that safe practices and codes of conducts are strictly followed in letter
and spirit. Departmental organization should focus on risk management
and mitigation and rules and regulations for occupational safety should be
clearly laid out and complied with.
KEY POINTS
• Anesthesiology is a pioneering specialty which has focused a lot on patient
safety to minimize risk and preventable harm to patients under its care.
The Anesthesia Patient Safety Foundation (APSF) established in the
United States of America (USA) has led the way in toward this path.
• Recently, the focus has been on the health hazards to the anesthesiologist
which can be divided mainly into physical, mental, and other hazards.
• Waste gas exposure is still a major problem in developing countries.
Using closed circuits and scavenging systems and proper air exchanges
and environmental control of operation theaters will reduce the risks to
the anesthesia workers.
• Availability of and correct placement of dosimeters and use of protective

gear in operating rooms have reduced radiation exposure hazard.
• Latex-free products have to be available in operating theaters for staff and
patients allergic to latex. Hand-washing should be done at the earliest
after contact with latex.
• All patients should be treated as potential infection risks and universal
precautions used to minimize the transmission of infectious agents.
• Continued exposure to stress can lead to mental, emotional, and physical
exhaustion, ultimately leading to a burnout. It is important to recognize
symptoms of stress early, so that modification of lifestyle can be initiated.
• Compared to other specialties, there is a higher incidence of substance
abuse in anesthesia due to the nature of job and easy availability of drugs.
The coworkers can be held legally responsible, if they do not report a
drug abusing/dependent colleague.
• Alarm fatigue, noise effects, hearing disability, and backaches due to
repeated manual handling of patients are recognized hazards.
• It is important to recognize the occupational health hazards and quality
measures implemented and audited to recognize, reduce, and manage
risks.
REFERENCES
1. McMechan F. Noted anesthetist dies a martyr to his skill. Curr Res Anesth
Analg. 1922;1:18.
2. Tankó B, Molnár L, Fülesdi B, et al. Occupational hazards of halogenated
volatile anesthetics and their prevention: review of the literature. J Anesth Clin
Res. 2014;5:426.
3. Özelsel TJ, Kim S, Buro K, et al. Elevated waste anaesthetic gas concentration
in the paediatric post-anaesthesia care unit. Turk J Anaesthesiol Reanim.
2018;46:362-6.
4. Ismail S, Khan FA, Sultan N, et al. Radiation exposure of trainee anaesthetists.
Anaesthesia. 2006;61:9-14.
5. Arii T, Uchino S, Kubo Y, et al. Radiation exposure to anaesthetists during
endovascular procedures. Anaesthesia. 2015;70:47-50.
6. Thomas I, Carter JA. Occupational hazards of anaesthesia. Contin Educ Anaesth
Crit Care Pain. 2006;6:182-7.
7. Accetta D, Kelly KJ. Recognition and management of the latex-allergic patient
in the ambulatory plastic surgical suite. Aesthetic Surg J. 2011;31:560-5.
8. Chaari N, Sakly A, Amri C, et al. Occupational allergy in healthcare workers.
Recent Pat Inflamm Allergy Drug Discov. 2010;4:65-74.
9. Hollnberger H, Gruber E, Frank B. Severe anaphylactic shock without
exanthema in a case of unknown latex allergy and review of the literature.
Pediatric Anesthesia. 2002;12:544-51.
10. Tannenbaum TN, Goldberg RJ. Exposure to anesthetic gases and reproductive
outcome. A review of epidemiologic literature. J Occup Med. 1985;27:659-68.
11. Sanfilippo F, Noto A, Foresta G, et al. Incidence and Factors Associated
with Burnout in Anesthesiology: A Systematic Review. Biomed Res Int.
2017;2017:8648925.
12. Horton JN, Harmer M. The selection of trainees. Baillière’s Clinical
Anaesthesiology. 1994;8:575-89.
13. Mayall RM. Substance abuse in anaesthetists. BJA Education. 2016;16:236-41.

14. Shuchisnigdha D, Claudio D. Alarm fatigue and its influence on staff
performance. IIE Transact Healthcare Syst Engin. 2015;5:183-96.
15. Anson JA, Vaida SJ, King TS, et al. Are We hurting ourselves? What is the
prevalence of back pain in anesthesia providers? J Clin Anesth. 2016;34:502-6.
16. Baxter AD, Boet S, Reid D, et al. The aging anesthesiologist: a narrative review
and suggested strategies. Can J Anaesth. 2014;61:865-75.
17. Jonathan DK. The impaired and/or disabled anesthesiologist. Curr Opin
Anaesthesiol. 2017;30:217-22.
18. Jena AB, Seabury S, Lakdawalla D, et al. Malpractice risk according to physician
specialty. N Engl J Med. 2011;365:629-36.
19. Lynch J, Appelboam R, McQuillan PJ. Survey of abuse and violence by patients
and relatives towards intensive care staff. Anaesthesia. 2003;58:893-9.
20. Hahn S, Hantikainen V, Needham I, et al. Patient and visitor violence in the
general hospital, occurrence, staff interventions and consequences: a cross‐
sectional survey. J Adv Nurs. 2012;68:2685-99.
21. Lepousé C, Lautner CA, Liu L, et al. Emergence delirium in adults in the post-
anaesthesia care unit. Br J Anaesth. 2006;96:747-53.
22. Gerald L, Wolf MD. Danger from OR Fires Still a Serious Problem. Newsletter
Anesth Patient Safety Found. 1999;14:6-7.
23. Alkhenizan A, Shaw C. Impact of accreditation on the quality of healthcare
services: a systematic review of the literature. Ann Saudi Med. 2011;31(4):
407-16.
24. McGinn PR. Practice standards leading to premium reductions. Am Med News.
1988;22.
Effect of Anesthesia on the Developing Brain 157
CHAPTER
11 Effect of Anesthesia on the

Developing Brain: A Review of
Recent Evidence
M Subrahmanyam, Gita Nath
INTRODUCTION
Pediatric anesthesia has come a long way since the first administration of
ether to an 8-year-old boy by Dr Crawford Long in 1942; and now millions of
children are given anesthesia every year, all around the world. The primary
focus in the latter part of 20th century was the avoidance of cardiac and
respiratory complications in the perioperative period. With increasing
awareness and widespread availability of pulse oximetry and capnography,
anesthesia in children has become very safe, with incidence of anesthesia-
related cardiac arrests ranging from 2 to 5 per 10,000 anesthetics.
In recent years, there have been concerns regarding the effects of
anesthetic medications on neural tissue. Ikonomidou first observed that
NMDA-receptor antagonism for just a few hours triggered widespread
apoptosis in neural tissue in the brain of developing rats.1 Following this
publication, a large body of evidence has accumulated concerning this topic.
In this article, we will discuss the pathophysiological basis of these effects,
examine the evidence from animal studies, and discuss its applicability to
humans. We will then look at the studies done in humans and attempt to
evaluate the possible association between anesthesia in early childhood and
long-term neurodevelopmental effects.
NEUROTRANSMITTERS IN THE BRAIN

Mediators of synaptic transmission in the brain are glutamate, GABA
(gamma-aminobutyric acid), acetylcholine, serotonin, dopamine, endo
cannabinoids, and endorphins. Among these, glutamate is the main
excitatory neurotransmitter; and acts on several types of receptors—
AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), NMDA
(N-methyl-D-aspartate), kainate, and metabolotropic receptors. All these
receptor types are involved in the process of synaptic plasticity, which is the
ability to strengthen or weaken synaptic pathways and thus the functions
of learning and memory. GABA on the other hand, is the chief inhibitory
neurotransmitter in the brain, and works by increasing the permeability of
the chloride channels and causing hyperpolarization of the cell membrane.
Table 1: Mechanism of action of anesthetic agents.

GABA Agonists •• Barbiturates
•• Propofol
•• Benzodiazepines
•• Etomidate
•• Sevoflurane, desflurane, isoflurane, etc.
NMDA Antagonists •• Ketamine
•• Nitrous oxide
µ-receptor Agonists Opioids
α2-receptor Agonists Dexmedetomidine
(GABA: gamma-aminobutyric acid; NMDA: N-methyl-D-aspartate)
Fig. 1: Timeline of neural development.
GABAA receptors are the main molecular target of benzodiazepines,

intravenous and inhalational agents as well as ethanol (Table 1).2
Neurodevelopment
In all mammals, there is a brain growth spurt during which a huge
increase in number of brain cells (neurogenesis) and synaptic connections
(synaptogenesis) takes place. The specific time varies between species;
in humans, the critical period starts toward the end of second trimester
of gestation, peaks at about 5 months after birth and lasts for 2–3 years
(Fig. 1). The number of brain cells is much more than required, and there
is a natural pruning process where excess neurons undergo apoptosis
or programmed cell death. Any imbalance in this process with excessive
apoptosis can lead to long-term effects on neurodevelopment. The control
mechanisms for synaptogenesis and pruning involve the glutamate (and
NMDA receptors) as well as GABA neurotransmitter-receptor systems.2 In
the absence of glutamate and GABA binding, the neurons downstream in
the pathway undergo apoptosis, which normally affects up to 1% of neurons
every day when it is at its peak rate.3
Both NMDA blockers such as ketamine, as well as GABA-ergic drugs,

which include most of the anesthetic drugs in use, have been associated
with increased apoptosis. If it is proven that anesthetic agents increase
apoptosis, that would form a basis for the assertion that general anesthesia
and sedation during the critical period of synaptogenesis could cause
temporary or long-term effects on brain function.3
EVIDENCE FROM ANIMAL STUDIES

In 1999, Ikonomidou et al. described a 15- to 40-fold increase in neuro
apoptosis in several areas of the brains of 7-day-old rats after exposure
to ketamine and other NMDA antagonists for several hours.1 This period
in rats is associated with peak synaptogenesis and neuroapoptosis, and is
roughly equivalent to the last trimester in human babies. Four years later,
a study by Jevtovic-Todorovic et al. showed that exposure to nitrous oxide,
isoflurane, and midazolam for 6 hours at clinical concentrations resulted
in a 20- to 60-fold rise in neuroapoptosis in multiple regions of the brain.4
In this landmark study, they also found long-term deficits in learning,
memory, and spatial discrimination in the surviving cohort of animals. It
is noteworthy that there were no signs of respiratory or metabolic distress
in the study animals, and no differences in blood gases compared to the
control group.
Following this, hundreds of animal studies have confirmed that acute
neurodegenerative histological effects and long-term neurobehavioral
deficits are caused by all commonly used GABA and NMDA-binding agents.
Neuronal changes have been detected by histological studies as well as
effects on specific biochemical changes (e.g. activated caspase-3 and the
presence of single-stranded DNA) in the apoptotic cells.3
The earlier studies were done on rats and mice, but subsequently, guinea
pigs and then piglets were studied. Compared to rats, synaptogenesis in
guinea pigs takes place over a much longer period and occurs mostly before
birth. Because guinea pigs are larger in size, it was possible to monitor
the mother invasively during isoflurane-N2O-midazolam anesthesia and
provide stable cardiorespiratory conditions for the mother and hence the
fetus.5 Similarly, piglets have a long period of synaptogenesis, both pre- and
postnatally. They were also stabilized during isoflurane-N2O-midazolam
anesthesia using invasive monitoring.6 Both these studies demonstrated
anesthesia-induced apoptosis during peak synaptogenesis, even with brief
periods of exposure.
In an attempt to see if similar effects are seen in animals more closely
related to humans, Rhesus monkeys have been studied. Isoflurane and
ketamine were found to cause dose and duration dependent increase in
apoptotic processes in specific areas of the brain, in late pregnancy and
neonatal period.7-9 Table 2 summarizes a representative selection of the
animal studies on this topic.
Table 2: Evidence from studies on animal models.

References Animals Drugs Results
Ikonomidou Rat Ketamine and 15- to 40-fold increase in
et al. 19991 other NMDA neuroapoptosis
antagonists
Ikonomidou Rat Ethanol Developing forebrain shows widespread
et al. 200010 apoptotic neurodegenerative changes
Jevtovic- Rat Midazolam, N2O, 20- to 60-fold increase in neuroapoptosis
Todorovic and isoflurane Long-term effects on memory,
et al. 20034 learning, and spatial discrimination
Fredriksson Mouse Ketamine and Apoptosis most pronounced with
et al. 200411 diazepam combination
Changes in learning abilities with
ketamine ± diazepam
Young et al. Mouse Ketamine and Apoptotic neurodegeneration with
200512 midazolam relatively mild exposure
Yon JH Rat Midazolam, N2O, Anesthesia-induced neurodegene
et al. 200513 and Isoflurane ration is highly age dependent, more
during peak synaptogenesis
Yon J-H Rat Midazolam, N2O, Anesthesia-induced neurodegene
et al. 200614 and Isoflurane + ration is reduced by melatonin
melatonin
Cattano Mouse Propofol Neuroapoptosis at a quarter of the
et al. 200815 dose required for surgical anesthesia
Viberg et al. Mouse Ketamine Changes in proteins involved in
200816 brain maturation
Irreversible behavioral changes in
adult mice
Zhang et al. Mouse Subclinical Neuronal apoptosis potentiated
200817 sevoflurane
Rizzi et al. Pregnant Midazolam, N2O, Midazolam, N2O, and isoflurane
20085 guinea pig isoflurane, and damaged fetal brain but not fentanyl
fentanyl
Rizzi et al. Piglets Midazolam, N2O, Even relatively brief exposure to
20106 and isoflurane anesthesia affects brain regions which
are at peak synaptogenesis
Slikker Rhesus Ketamine Neuronal cell death at 122 days gestation
et al. 20077 monkey and 5 days after birth, but not later
Zou et al. Newborn Ketamine Nerve cell death after 9- and 24-hours’
20098 rhesus exposure, but no change at 3 hours
monkeys
Brambrink Neonatal Isoflurane 5 h exposure to 1 MAC isoflurane
et al. 20109 rhesus caused 13-fold increase in
macaque neuroapoptosis
Creeley Rhesus Propofol and Neuronal cell death at 120 days
et al. 201418 macaquesIsoflurane gestation and 5 days after birth when
exposed to propofol for 5 hours
Propofol causes less apoptosis than
isoflurane
(MAC: minimum alveolar concentration; NMDA: N-methyl-D-aspartate; N2O: nitrous
oxide)
Despite the enormous amount of preclinical evidence, which has

demonstrated that anesthetic agents do affect brain synaptogenesis and
apoptosis during critical periods of neurodevelopment, applicability of this
data in human scenarios is still not clear. One point which must be kept in
mind is that the time scale of development of rodents as well as nonhuman
primates is very different from human. That means exposure to anesthetic
agents to a few hours during an experiment is probably equivalent to several
days’ exposure of human babies to anesthesia, which does not really happen
in practice.
The relevant questions to be answered are:
• Are there apoptotic effects in humans at clinical concentrations?
• Are the effects temporary or long-term?
• Are there sensitive methods of detecting these effects?
• Even if there are detrimental effects, are they significant enough to affect
intellectual, social, and emotional capabilities of the children?
CLINICAL STUDIES
Retrospective Studies
One approach to this problem is to see if administration of anesthesia in
early childhood correlates with any current cognitive or behavioral adverse
effects. In such studies, anesthesia may not be standardized but it is possible
to obtain a large study sample. Outcome measures can include the following:
• School test results
• Assessment for learning disability
• Necessity for individualized education program:
▪▪ For behavioral or emotional disorders
▪▪ For speech or language impairment
• Diagnosis, e.g. attention deficit hyperactivity disorder, mental retardation,
and autism.
Drawbacks of this Approach

• Anesthetic techniques used several years ago are probably different
from currently used protocols. Also, details of the anesthetic and any
perioperative events may not be available.
• Effects of surgical stress cannot be separated from the effect of anesthesia.
• The indication for surgery may have exerted deleterious effects on the
baby. Children requiring surgery, especially multiple procedures or
prolonged operations, may already be prone to learning difficulties.
• Other perinatal problems such as prematurity, low birth weight,
perinatal hypoxia, cardiac, gastrointestinal, or central nervous system
(CNS) disorders may all be confounding factors.
Danish Birth Cohort Study

From national birth registers in Denmark, the records of all births from 1986
to 1990 were extracted. Among these children, 2,689 underwent repair of
inguinal hernia in infancy. The control group was an age-matched, randomly
selected population sample of 14,575 children. When the ninth-grade test
scores were compared after compensating for known confounders, there
was no difference between the groups.19 From the same birth cohort, 779
children had been operated for pyloric stenosis before they were 3 months
old. These were compared to another similar control group of 14,665
children. Again, there was no difference in the ninth-grade test scores after
adjusting for known confounders.20 However, in both these studies, there
was a slightly increased proportion of children who did not attain test scores
(odds ratios of 1.13 and 1.37, respectively). Test scores were not attained
among dropouts, children who attended alternative schools and children
with functional limitations, suggesting that a subgroup of children who had
early surgery could potentially be developmentally disadvantaged.
Data from Netherlands Twin Registry

Educational achievement and cognitive problems were compared at age 12
in 1,143 monozygotic twin pairs from the national registry. Lower scores were
found in children who were exposed to anesthesia before age 3 than those
not exposed, but interestingly, in each twin pair, the scores of the exposed
child were not different from their unexposed co-twin. The conclusion was
that early anesthesia may be a marker of a child’s vulnerability for learning
problems later in life, whether or not they were exposed to anesthesia.21
Mayo Clinic–Olmstead County Studies

The study population included all children born from 1976 to 1982 in
five identified Olmstead County townships, who remained in the same
community at the age of 5 years. Of the 5,357 children included, 593
received anesthesia before 5 years of age. There was a higher incidence of
learning disabilities in those children who had two or more exposures to
general anesthesia with but this was not so with a single exposure.22 From
the same population, 350 children who had general anesthesia before age
2 were compared to 700 control subjects. Multiple exposures were found
to increase the risk of learning difficulty but not of behavioral disorders.23
In the same population, multiple exposures to general anesthesia before
age 2 increased the risk of attention-deficit/hyperactivity disorder (ADHD).24
New York—Medicaid Study

All children born in New York State from 1999 to 2001 and covered by
Medicaid system were identified. In 383 children who underwent inguinal
hernia repair before age of 3 years, the risk of developmental or behavioral

disorder was more than double compared to 5,050 children who were not
exposed to anesthesia.25 From the same study population but extending the
period to 1999–2005, 5,824 twin pairs were identified. Among these, 668
procedures in 304 children were documented before age of 3 years. These
children had 60% higher incidence of developmental and/or behavioral
disorders but a causal relationship with anesthesia could not be determined.26
Other Studies
Another group from Iowa studied children with no risk factors for CNS
disorders, who underwent three commonly performed surgical procedures
before age of 1 year. The standardized achievement scores of these 58
children did not differ from normal, but a greater than expected percentage
had scores below the 5th percentile.27 The same group examined the MRI
brain of 17 children between 12 and 15 years age, who had surgery before
age 1 and did not have any CNS risk factors. Compared to 17 normal
controls, there was decreased white matter integrity and volume in broadly
distributed areas, which may or may not be attributed to surgery and
anesthesia during infancy.28
A population-based cohort study was conducted in Ontario where
developmental outcomes at entry into primary school were correlated with
exposure to anesthesia. There were 28,366 children who underwent surgery
before they completed EDI (early development instrument for children
aged 5–6 years) and they were compared to 55,910 children unexposed to
anesthesia. There was a very slightly increased risk of early developmental
vulnerability in exposed children. In this study, contrary to previous reports,
first exposure before 2 years of age or multiple exposures to surgery were
not associated with a higher risk of adverse child development.29
Prospective Studies
It is difficult to avoid confounding factors in such studies, for instance
the influence of the surgical condition necessitating surgery, possible
associated congenital factors, and birth factors such as prematurity and
so on; which may by themselves increase learning difficulties. For these
reasons, three prospective studies were designed to elucidate this issue,
namely the General Anesthesia compared to Spinal anesthesia (GAS) study,
the Pediatric Anesthesia and Neurodevelopmental Assessment (PANDA)
study, and the Mayo Anesthesia Safety in Kids (MASK) study.
The General Anesthesia Compared to Spinal Anesthesia Study

This was registered in 2008,30 and designed as a prospective, multisite,
observer blind, randomized, controlled, and equivalence trial. It included
infants less than 60 weeks’ postmenstrual age, born after 26 weeks’ gestation
who needed repair of inguinal hernia. The general anesthesia (plus caudal
or ilioinguinal block) group was compared with the regional anesthesia (RA)
group (spinal, spinal with caudal, spinal with ilioinguinal block, or caudal
alone). The primary outcome was the Wechsler IQ score at 5 years of age;
and the secondary outcomes were postoperative apnea and the cognitive
assessment with Bayley developmental scale at age of 2 years.
The trial enrolled a total of 722 infants, 363 to RA and 359 to general
anesthesia. Anesthesia lasted for a mean of 54 minutes in both groups.
Apnea in the early postoperative period was reduced in the RA group31
but there was no difference in the neurodevelopmental assessment at
age of 2 years.32 This year, the analysis of the 5-year outcome has been
published. The full-scale IQ score was measured on Wechsler Preschool
and Primary Scale of Intelligence, the most validated and reliable measure
of general intellectual ability; and the two groups displayed strong evidence
of equivalence. A range of other behavioral and neurocognitive outcomes
showed no significant differences.33 The drawback of this study was that the
study population was strongly male dominated, but the gender distribution
was similar between the groups.
Pediatric Anesthesia and Neurodevelopment Assessment Study

This was a multisite large-scale study conducted at four major pediatric
centers in the US. Sibling pairs with age difference less than 36 months
were included, both of whom were between 8 and 15 years at the time of
the study. One of each pair had been exposed to anesthesia for inguinal
hernia surgery before 3 years of age, and the other was not. This design
was chosen to minimize the effects of genetic, environmental, and other
socioeconomic factors between the study and control groups.34 All children
were rigorously tested at ages between 8 and 15 years of age with a battery of
neuropsychological tests, by trained pediatric neuropsychologists who were
blinded to exposure status of the subjects. In total, 105 sibling pairs were
assessed, and the mean age at assessment was 10.6 years in the exposed
group versus 10.9 in the unexposed group.35
All the anesthetics were with inhalational agents and lasted 20–240
minutes (mean 80 minutes). The groups did not differ statistically in
learning/memory, motor/processing speed, visuospatial function, attention,
executive function, language, or behavior. Longer exposure to anesthesia of
120 minutes or more was not associated with larger IQ differences, but there
were only a small number of children in this subgroup. Since these were
healthy children at the time of exposure, the effects of repeated or prolonged
anesthetic exposure, and exposure of children in vulnerable groups still
need to be elucidated.35
Mayo Anesthesia Safety in Kids Study

This was a prospective study involving children who were born in
Olmstead County between the years 1994 and 2007. Using a propensity
guided approach, 997 were sampled and neuropsychological testing was
done at ages 8–12 years or 15–20 years. These age ranges were selected as
representing different stages of development of the children. All the exposed
children had their first exposure to anesthesia before age of 3 years. To
minimize confounding factors, children who had single or no exposures
were recruited to be best matched with multiply exposed children on a
variety of characteristics potentially affecting the outcomes of interest.36
Of the 997 children tested; 411, 380, and 206 were not exposed, had
only one exposure and had multiple exposures, respectively. There was no
significant difference in the primary outcome which was general intelligence
using the Wechsler Abbreviated Scale of Intelligence. As to secondary
outcomes, fine motor abilities and processing speed were decreased in
those who had multiple but not single exposures; however, there were
no differences in other domains. Parents of children who had multiple
exposures reported greater difficulties with reading, behavior, and executive
function.37
The authors thus concluded that there were no deficits in general
intelligence with even multiple exposures to anesthesia before the age of
3 years. However, behavioral and learning difficulties may be associated
with multiple, but not single exposures.
MATERNAL ANESTHESIA AND ITS EFFECTS

ON THE FETUS
Since synaptogenesis and apoptosis in primates and humans start in the
third trimester of pregnancy, it is important to consider whether maternal
anesthesia has any long-term effects on the fetal brain. A 2012 review
of this topic summarized the available research findings and discussed
fetal susceptibility according to gestational age.38 In the first trimester of
pregnancy, the fetus is considered susceptible to teratogenesis, since this
is the period of organ formation. However, the incidence of major birth
defects was found to be about 2–4%, which is not higher that the baseline
incidence.39-41 The only exception is a higher rate of neural tube defects,
but the confounding factor here is that maternal fever by itself is a risk
factor for these defects; and most surgical conditions requiring surgery in
early pregnancy are associated with fever. The only anesthetic agent with
convincing teratogenic data is nitrous oxide, which is associated with ocular
and skeletal defects in rodents and a higher incidence of preterm births and
spontaneous abortions in human studies.42-45
The second trimester has traditionally been thought to be the safest

period for maternal anesthesia. But this is also a time when the processes of
neurogenesis and neuronal migration are in full swing, and synaptogenesis
is starting. Gestational exposure to anesthetic agents in rats, guinea pigs,
and macaque monkeys has been associated with histological evidence of
cell death as well as behavioral abnormalities.5,7,46,47 Perhaps, the time has
come for us to re-evaluate the consequences of anesthetizing the pregnant
patient in the second trimester.
Coming to the third trimester, rodent studies have shown that 3%
isoflurane caused neurodegeneration in the fetal hippocampus but not
1.3% isoflurane, showing that the effect may be dose dependent.48 There
are very few clinical studies, but a birth cohort study looking at the
Rochester Epidemiology Project database compared the incidence of
learning difficulty in children whose mothers received general anesthesia
or RA during cesarean delivery. Incidence of learning difficulties was not
higher in the cohort exposed to general anesthesia during birth. There are
several issues which limit the validity of this study—the data is from 1976
to 1982, anesthetic as well as obstetric practice has changed since then
and the criteria for diagnosing learning difficulties have also changed.49
However, given that general anesthesia for cesarean delivery is given only
for specific indications; and also, the duration of exposure is short—only till
the cord is clamped, it does not seem necessary to alter current anesthetic
practice in this situation. Regarding the use of Entonox for labor analgesia,
preclinical studies have shown behavioral teratogenicity50,51 and we do not
know the long-term neurodevelopmental effect of exposure to nitrous oxide
at subanesthetic concentrations for several hours.
To summarize the available information on prenatal exposure to
anesthetics [American College of Obstetricians and Gynecologists (ACOG)
opinion, 2019]:52
• None of the anesthetic agents in current use has displayed any teratogenic
effects at any gestational age, as long as they are used in standard doses
and concentrations.
• There is no evidence that in utero human exposure to anesthetic or
sedative agents has any effect on the developing fetal brain; and there
is no animal data showing that exposure of <3 hours duration has any
such effect.
• Elective surgery should be postponed to after the pregnancy; but
medically necessary surgery should not be denied or delayed, regardless
of trimester.
• Maternal cardiopulmonary physiology should be optimized during
the procedure. Premature onset of labor should be watched for and
administration of steroids for fetal benefit should be considered.
• There is no data about the neurodevelopmental effects of prolonged
exposure, for instance during fetal surgery or Entonox for labor.
Potential Protective Role for Dexmedetomidine

Dexmedetomidine is an anesthetic adjuvant drug, which acts as a highly
selective α2-agonist in the locus coeruleus where it produces hypnosis and
anxiolysis; and in the spinal cord where it produces analgesia. It has no effect
on either GABA or NMDA receptors. It has the advantages of maintaining
normal respiratory patterns and reducing the requirements of anesthetic
and analgesic drugs. Additionally, there is considerable clinical experience
with this drug in pediatric practice.
In 2009, Sanders et al. exposed neonatal rats to dexmedetomidine
and demonstrated that it did not increase apoptosis.53 In fact, when
coadministered with isoflurane, dexmedetomidine suppressed the increased
apoptosis caused by isoflurane in a dose-dependent manner, back to
baseline level. It also prevented the neurobehavioral effects of isoflurane
in surviving cohorts of animals.54 Since the publication of these papers, 10
further animal studies have been published, in rats, sheep, and monkeys.
Dexmedetomidine did not increase apoptosis in eight studies; in the
remaining two papers, apoptosis was seen only at very high doses. In fact,
this agent ameliorated the neuroapoptotic effects of isoflurane, propofol,
and ketamine.3
There are now two clinical multicenter studies, which have now been
started to assess the safety and feasibility of dexmedetomidine as a major
component of anesthesia when prolonged surgery is necessary in the infant.
The T-REX study (Toxicity of Remifentanil and dexmedetomine) is using
these two drugs along with a caudal block for surgery in the lower abdomen
or lower extremity lasting at least 120 minutes in 60 infants. This is primarily
a feasibility study, looking at the ability to complete the surgery without
excessive hemodynamic compromise (bradycardia and hypotension), or
patient movement causing suboptimal surgical conditions. This study will
also assess the safety of this regimen. If deemed feasible; a further study will
be planned, prospectively comparing the dexmedetomidine-remifentanil
regimen with a standard anesthetic technique, i.e. sevoflurane; with
neurodevelopmental follow-up.55
The second study which is ongoing deals with safety and pharmacokinetics
of dexmedetomidine during infant cardiac surgery. Here, dexmedetomidine
is given in addition to a standardized anesthetic based on fentanyl and
isoflurane. A total of 116 infants will be enrolled, from birth till 6 months
of age undergoing open heart surgery for repair of ventricular septal
defect, tetralogy of Fallot, or arterial switch operation. Safety events, mainly
cardiovascular, will be assessed as the primary outcome. This data will be
used to plan a randomized, prospective trial comparing dexmedetomidine
to saline placebo, added to a standardized anesthetic regimen; and
neurodevelopmental assessment at age 2 years will be the primary outcome.56
CONCLUSION
There is overwhelming evidence from animal studies, nonhuman primate
studies, and retrospective human studies that both intravenous (midazolam,
propofol, barbiturates, etomidate, and ketamine) and inhalational
(sevoflurane, isoflurane, and nitrous oxide) anesthetic agents cause dose
and duration dependent apoptotic changes, if administered during the
period of brain spurt or synaptogenesis; due to their effects on GABA
receptors, NMDA receptors, or both. The vulnerable period in human
fetuses and children starts in the third trimester, peaks in early infancy,
and lasts for 2–3 years after birth. Opiates (morphine, fentanyl, alfentanil,
and remifentanil) and α2-agonists (dexmedetomidine and clonidine) do not
have such an effect.
We have obtained results from the three major prospective studies—
the GAS, PANDA, and MASK studies, which have all confirmed that a
single exposure to anesthesia of about an hour is not associated with any
intellectual or behavioral deficits. The effects of prolonged or multiple
exposures to anesthesia, as well as patients whose brains are vulnerable, e.g.
the fetus, babies with complex neonatal surgical conditions, and critically
ill infants who need sedation in the ICU and so on will need further study.
For young children who need surgery, the surgical indication should
be balanced against the possibility of neurodevelopmental effects from
exposure to anesthetic agents. Based on results from recent studies, we can
now assure parents that anesthesia of short to moderate duration has no
demonstrable long-term effects. However, for more complex or prolonged
operations, the need and urgency for surgery have to be weighed against
the small risk of cognitive or behavioral problems.
Maternal exposure of short duration to anesthetic or sedative drugs
at standard doses or concentrations has not been shown to produce any
teratogenic or fetal neurodevelopmental effects, regardless of gestational
age; except for nitrous oxide, which has teratogenic effect in rats and
spontaneous abortions and preterm births in humans.
Dexmedetomidine is emerging as a neuroprotective agent against the
detrimental effects of conventional anesthetic agents on neuroapoptosis,
as shown by preclinical studies on animal models. If the ongoing clinical
trials are successful, dexmedetomidine will be a welcome addition to our
armamentarium to protect vulnerable brains—the infant during prolonged
or complex surgery as well as the fetus during maternal anesthesia.
KEY POINTS
• In animal models and retrospective human studies, inhalational and
intravenous anesthetic agents cause dose and duration dependent
apoptotic changes, if administered during the period of synaptogenesis.
• They cause these changes due to their effects on NMDA and/or GABA
receptors.
• The vulnerable period in human fetuses and children starts in the third
trimester, peaks in early infancy, and lasts for 2–3 years after birth.
• The GAS, PANDA, and MASK studies have all confirmed that there are
no intellectual or behavioral deficits associated with a single anesthetic
exposure. The effects of prolonged or multiple exposures to anesthesia
need further research.
• Maternal exposure of short duration to anesthetic or sedative drugs at
standard doses or concentrations has not been shown to produce any
teratogenic or fetal neurodevelopmental effects, regardless of gestational
age; with the exception of nitrous oxide, which has teratogenic effect in
rats and spontaneous abortions and preterm births in humans.
• Dexmedetomidine is emerging as a neuroprotective agent against the
detrimental effects of conventional anesthetic agents on neuroapoptosis.
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Weaning from Mechanical Ventilation 173
CHAPTER
12 Weaning from Mechanical

Ventilation
Saurabh Kumar Das, Sumit Ray
INTRODUCTION
Mechanical ventilation (MV) can often get complicated with ventilator-
associated pneumonia (VAP), sinusitis, injury to the upper airway, muscle
weakness, prolonged intensive care unit (ICU) or hospital stay, and
mortality. On the other hand, reintubation after premature extubation
causes increased morbidity and mortality.1 So timely weaning is a very
important and crucial step in the care of critically ill patients who require
intubation and invasive MV.
DEFINITIONS
There is no universally accepted definition of weaning. It can be best
defined as “liberation from MV to enable unassisted or minimally-assisted
spontaneous respiration”.
WIND (Weaning according to a New Definition) Study defined weaning
as:2
• “For intubated patients, separation attempt from MV—a spontaneous
breathing trial (SBT) with or without extubation, or an extubation
directly performed without identified SBT (whatever the type—planned
or unplanned extubation).”
• “For tracheotomized patients, separation attempt from MV—24 hours or
more with spontaneous ventilation through tracheostomy without any
MV.”
• Weaning success is defined as “extubation and the absence of ventilatory
support 48 hours following the extubation”.3
• Weaning failure is defined as one of the following:
▪▪ When the SBT fails
▪▪ There is requirement for reintubation and/or resumption of ventilatory
support following successful extubation; or
▪▪ When the patient dies within 48 hours following extubation.3
• Failure of SBT can be defined by both, objective and subjective indices

as follows:
▪▪ Objective indices of failure include tachycardia, tachypnea, hyper
tension, hypotension, hypoxemia or acidosis, and arrhythmia.
▪▪ Subjective indices include agitated, distressed or depressed mental
status, diaphoresis, and evidence of increasing respiratory effort.3
• Simple weaning refers to “patients who proceed from initiation of
weaning to successful extubation on the first attempt without difficulty”.4
• Difficult weaning is when “patients who fail initial weaning and require
up to three SBTs or as long as 7 days from the first SBT to achieve successful
weaning”.4
• Prolonged weaning means that the “patient failed at least three weaning
attempts or required 7 days of weaning after the first SBT”.4
• Prolong MV means that the “duration of MV exceeds more than 21 days
for at least 6 hours a day”.
Weaning denoted a gradual process. “liberation” or “discontinuation”
may be better terms than “weaning”, because they suggest a quick withdrawal
of ventilator support. Therefore, “liberation” or “discontinuation” is a more
favored method than “weaning” because latter may actually unnecessarily
prolong ventilation.
STAGES OF MECHANICAL VENTILATION

A series of six stages can be identified, that starts from “intubation followed
by initiation of MV, starting of the weaning attempt, to the final liberation
from MV and successful extubation”.
These six stages are defined as follows:3
1. Treatment of acute respiratory failure (ARF) which is defined as “period
of treatment and resolution of the disease that caused respiratory failure
and necessitated initiation of MV”.
2. Anticipation of weaning is that point of time when physician thinks that
“liberation from MV can be initiated”.
3. Assessment of readiness to wean is daily “assessment of probability of
successful weaning”.
4. Spontaneous breathing trial is “assessment of patient ability to breathe
spontaneously”.
5. Extubation is “removal of endotracheal tube (ETT)”.
6. Reintubation is required if “patient cannot maintain adequate spon
taneous breath after extubation”.
Anticipation of Weaning or When to Wean?

Weaning should be considered as soon as the stage one of MV, i.e.
treatment of respiratory failure is achieved. However, in real life scenario,
the anticipation is not always easy. It is estimated that 40–50% of the total
duration of MV is spent in the process of weaning.5 Interestingly, one
observational study found that almost 50% of patients who self-extubated
during weaning did not require reintubation.6 This suggested that many
patients were kept on MV longer than was necessary. According to another
observational study, delay of extubation can increase mortality by 15%.7
Assessment for Weaning Readiness

Assessment of weaning readiness should include the evidence of recovery
from the disease process that prompted MV. The patient should be able
to protect airway that should be evident by ability to cough adequately.
The tracheobronchial secretions should also be minimal. Other desired
prerequisites for weaning are:3,8-10
• Stability of cardiovascular status with heart rate ≤140 beats/min and
systolic blood pressure (SBP) 90–160 mm Hg, none or minimal need
for vasopressors
• Stable metabolic status
• Adequate oxygenation as evident by arterial oxygen saturation (SaO2)
90% on fraction of inspired oxygen (FiO2) ≤ 0.4, partial pressure of
arterial (PaO2)/FiO2 ≥150 mm Hg, and positive end-expiratory pressure
(PEEP) ≤ 8 cm H2O
• Adequate pulmonary function with respiratory rate ≤ 35 breaths/min
• Maximum inspiratory pressure ≤ 20–25 cm H2O
• Tidal volume >5 mL/kg
• Vital capacity >10 mL/kg
• Respiratory rate and tidal volume ratio should be less than 105 breaths/
min/L
• There should be no significant respiratory acidosis
• Patient should be conscious with adequate mentation
• Patient should have stable neurological status with none or minimal
sedation.
Various parameters and weaning criteria have been developed to
assist physician for assessment of weaning readiness. However, no single
parameter should be used in isolation. These parameter and criteria
should be used in conjugation with other parameter and in appropriate
clinical setting. Commonly used weaning parameters are enumerated in
Table 1.
Combined Weaning Indices

Combination of weaning parameters has better accuracy than individual
parameters.
Table 1: Common weaning parameters.

Parameters Measurements
Simple ventilatory parameters 11
•• Vital capacity (VC)
•• Minute ventilation
Oxygenation •• PaO2/FiO2
Respiratory muscle strength11 •• Maximum inspiratory pressure (MIP)

•• Maximum expiratory pressure (MEP)
Central respiratory drive12 •• Airway pressure developed 100 ms after
the beginning of inspiration against an
occluded airway (P0.1)
Respiratory muscle reserve13 •• Maximal voluntary ventilation/minute
ventilation (MVV/MV)
•• Mean transdiaphragmatic pressure per
breath/maximal transdiaphragmatic
pressure (Pdi/Pdimax)
Pattern of spontaneous breathing11 •• Respiratory rate/tidal volume (f/Vt)
rapid shallow breathing
Integrated multiple variables index11 •• P0.1 × f/Vt
•• Compliance, rate, oxygenation, and
pressure
Pulmonary measurements •• Static compliance is tidal volume divided
by difference of plateau and positive
end-expiratory pressure. A value of
more than 30 mL/cm H2O indicates
adequate lung compliance.
•• Airway resistance is difference of
peak inspiratory pressure and plateau
pressure. If it is less than 5 cm H2O/L/
sec, it indicates low resistance.
(FiO2: fraction of inspired oxygen; PaO2: partial pressure of arterial)
Simplified Weaning Index

It evaluates efficiency of gas exchange and ventilator endurance. It can be
calculated as:
fmv [(PIP–PEEP)/MIP] × PaCO2/40
where fmv is ventilator frequency, PIP is peak inspiratory pressure, and MIP
is maximum inspiratory pressure. If it is <9/min, it is highly predictive of
weaning success and if >11/min, it predicts probability of weaning failure.
Compliance Rate Oxygenation and Pressure Index14

Dynamic compliance × maximum inspiratory pressure × (PaO2/PAO2)/
respiratory rate.
Compliance rate oxygenation and pressure (CROP) index of > 13 mL/

breath/min predicts of weaning success.
Rapid Shallow Breathing Index11

In the year 1991, Yang and Tobin described rapid shallow breathing index
(RSBI) as the ratio of respiratory rate to tidal volume, with a threshold value
of >105 breaths/min/L being highly predictive of weaning failure, while
RSBI <105 breaths/min/L is associated with weaning success.
CONVENTIONAL METHODS OF WEANING

Abrupt Discontinuation
Approximately, 75% of mechanically ventilated patients whose underlying
disease leading to respiratory failure has either improved or been resolved
can undergo abrupt liberation from MV. The remaining patients will need
progressive withdrawal from MV.15
Pressure Support Ventilation

Pressure support ventilation (PSV) is a mode of MV commonly used during
the weaning process in 21% of patients.3 The pressure support (PS) is titrated
to generate tidal volume of 6–8 mL/kg. It is then reduced by 2–4 cm H2O
every 30–60 minutes. Patient can be extubated when PS is less than 8 cm
H2O and with adequate tidal volume and respiratory rates.16
Spontaneous Intermittent Mandatory Ventilation

Spontaneous intermittent mandatory ventilation (SIMV) weaning is done by
gradually reducing the mandatory rate. In most trials, the mandatory rate
was reduced by 2–4 per minute on a twice-daily basis, or more frequently if
tolerated. The end-point for SIMV is a rate of 4–5 minutes, for considerable
periods of time. Patients who meet preset criteria are then extubated.16
Spontaneous Breathing Trial

It assesses the patient’s ability to breathe spontaneously on nil or minimal
ventilator support. Strategies to perform SBT include.17
• T-piece trial uses a T-piece to supplement oxygen through an ETT.
• A continuous positive airway pressure (CPAP) is used during SBT.
• Spontaneous breathing trial with low level of PS (5–8 cm H2O) or
automatic tube compensation (ATC).
Duration of SBT should be at least 30 minutes but should not exceed
120 minutes.18 A recent study among 1,153 patients found that a SBT
Flowchart 1: A common algorithm for the transition from mechanical ventilation to

spontaneous breathing (SBT denotes spontaneous breathing trial).
of 30 minutes duration, compared with 2 hours of T-piece ventilation,

led to significantly higher rates of successful extubation.19 Flowchart 1
depicts a common algorithm for the transition from MV to spontaneous
breathing.20
COMPARISON OF DIFFERENT CONVENTIONAL

MODES OF WEANING
A randomized controlled trial (RCT) involving 456 patients determined
that SIMV is associated with prolonged weaning as compared to PS or
T-piece trial (5.7 ± 3.7 days PSV vs 9.9 ± 8.2 days SIMV).10 Another study
on 546 medical-surgical patients reported that SIMV prolonged the weaning
process in comparison to PSV and T-piece trial.15
Several trials have examined the methods of undertaking an SBT. They
found no difference in the percentage of patients who had a successful
SBT or successful extubation when a T-tube trial was compared with
different levels of PS, or the CPAP.19,21-23 Due to dynamic hyperinflation,
chronic obstructive pulmonary disease (COPD) patients are more likely
to pass a 30 minutes SBT with 5–7.5 cm H2O CPAP as compared to a
T-piece.24
VENTILATOR MODES FOR WEANING

Automatic Tube Compensation
Automatic tube compensation is a ventilatory mode, which overcomes the
resistance offered by an ETT. It continuously calculates tracheal pressure
via a closed-loop control. It is claimed that ATC is superior to PSV as the

intratracheal pressure is measured at the carinal end of the ETT to control
flows, whereas, in PSV, pressure is monitored at the Y-piece of the ventilator
circuit or close to the expiration valve. It may be useful during situations when
high levels of PSV are required to reduce workload, with overcompensation
resulting in discomfort and dyssynchrony.25 In a randomized trial, it was
found that ATC was not able to overcome the pressure-time product
associated with triggering, and that PSV was as effective as ATC at 100%.26
A study tried to address the question whether overcoming ETT resistances
is really necessary to assess a patient’s readiness for extubation. The work of
breathing dissipated against the ETT was measured and it was found that it
represented around 10% of the overall work performed by the patient. This
increase in work load was no different from the resistance offered by the
upper airways immediately after extubation.27
Proportional Assist Ventilation

It provides pressure, flow, and volume assistance in proportion to the
patient’s spontaneous effort. The flow, volume, and pressure assistance is
directly proportional to patient’s effort. The operator sets the ventilator’s
volume and flow assist at approximately 60–80% of patient’s elastance and
resistance. The ventilator then generates proportional flow and volume
assist to augment the patient’s own effort.
In comparison to PSV and CPAP, there was no substantial benefit in
oxygenation, pressure time product, and other physiological variables.
Only when CPAP was combined with proportional assist ventilation (PAV),
substantial changes of studied parameters were noted.28
Adaptive Support Ventilation

Adaptive support ventilation (ASV) automatically adapts to the inspiratory
pressure and respiratory rate of the patient by a closed-loop system to
provide the target minute ventilation with minimum work of breathing
on the part of the patient. An algorithm is used to select the optimal
combination of respiratory rate and tidal volume which is associated with
the least work of breathing (based on the Otis equation).
In passive patients, ASV is an adaptive pressure-controlled ventilation,
which, in spontaneously breathing patients, switches to an adaptive PSV.29
An RCT compared the duration of ventilation with ASV and pressure
assist/control ventilation and found significantly shorter median ventilation
duration and weaning duration in ASV group. Patients in this group also
required fewer total number of manual settings on the ventilator to reach
the desired pH and PaCO2 level. The number of successful first attempt
extubation was also significantly higher in the ASV group. However, weaning
success and 28 day mortality were comparable between the two groups.30
Another study in patients with chronic obstructive airway disease also
demonstrated similar findings.31
SmartCare™
The SmartCareTM /PS system is an automated clinical closed-loop system,
which is designed to maintain patient’s spontaneous breathing in a
comfortable zone of normal ventilation and to automatically wean by
reducing the inspiratory support. The patient’s ventilatory status is
classified into eight categories, and some predefined measures are taken
to bring the patient back into a range called “normal ventilation”, or the
zone of respiratory comfort. “Adapt” is a weaning phase in which PS
is gradually decreased, while continuously checking if the patient can
tolerate the new level or not. If he/she is comfortable, the support level is
reduced further, if not, it is increased back to an appropriate level. When
the patient is weaned to the lowest level of support, an SBT is performed
while continuously observing the patient. This phase is called “observe”.
Spontaneous breathing frequency, spontaneous tidal volume, and end tidal
CO2 are used to adjust ventilator support. A randomized trial compared
SmartCareTM with respiratory physiotherapy–driven weaning and found
no superiority of SmartCareTM over respiratory physiotherapy–driven
weaning.32
WEANING PROTOCOL
The concept of ventilator weaning protocols, especially for nonphysician
respiratory care providers, became popularized with the 2001 publication
of recommendations of a task force on ventilator discontinuation.18
Various studies evaluated efficacy of weaning protocol and found that it
hastens weaning, decreases the duration of MV, and sometime duration
of hospitalization.8,33,34 A meta-analysis of the weaning protocol including
11 RCTs that totaled 1,971 patients found that although there was no
difference in mortality rate, weaning protocols were associated with a
22–25% reduction in the mean duration of MV.35
Flowchart 2 is an example of a weaning protocol.36
WEANING FAILURE
Around 20–30% of mechanically ventilated patients are considered difficult
to wean. Management of difficult weaning requires identification of risk
factors, pathophysiology, and optimization of such conditions.
Flowchart 2: Example of mechanical ventilation weaning protocol flow diagram.
(FiO2: fraction of inspired oxygen; PaO2: partial pressure of arterial; SBT: spontaneous
breathing trial; PEEP: positive end-expiratory pressure; SaO2: arterial oxygen saturation;
BP: blood pressure)
Some of common risk factors for difficult weaning are:

• Failure of SBT for two or more times
• Chronic heart failure
• Partial pressure of arterial carbon dioxide >45 mm Hg
• Multiple coexisting disease
• Poor cough
• Upper-airway pathology
• Age ≥65 years
• APACHE II (Acute Physiology and Chronic Health Evaluation II) score
>12 on day of weaning
• Patient in medical, pediatric, or multispecialty ICU
• Pneumonia as cause of respiratory failure.
The pathophysiology of weaning failure is complex and often multi
factorial. Therefore, determining the reason and subsequently formulating
a management strategy require a dedicated physician with in-depth
knowledge of the pathophysiology of weaning failure. A systematic approach
of diagnosis and management can be outlined as follow.
Pathophysiology Related to Airway

Various factors related to airway may predispose to weaning failure. A narrow
ETT increases airway resistance and work of breathing leading to weaning
failure. Therefore, sometime it is necessary to replace the ET tube with a
tube with bigger diameter. Glottic edema requires administration of steroids

to reduce inflammation. “leak test” can be done to diagnose tracheomalacia,
particularly in patient who are intubated for a longer time. Increased airway
secretions and retention of sputum should be managed with mucolytics,
humidification, chest physiotherapy, and control of infections.
Pathophysiology Related to Lung and Respiration

The success of weaning depends on the ability of the respiratory muscles
to withstand the load placed upon it. This respiratory load is a function of
the resistance and compliance of the ventilator pump. Pathophysiological
conditions that increase resistance (bronchoconstriction) or reduce
compliance (excessive lung water, pneumonia, pulmonary hemorrhage,
chronic lung conditions, pleural effusion, and collapse consolidation) may
predispose to weaning failure.
Management of these conditions includes adequate bronchodilator
for bronchoconstriction, diuretics for pulmonary edema, appropriate
antimicrobials for pneumonia, evaluation and treatment of connective
tissue disorder or vasculitis, optimization of chronic lung conditions, pleural
tapping for effusion, etc. Sometime inappropriate ventilator setting may
be cause of increase work of breathing, e.g. inadequate inspiratory flow,
inappropriate trigger, and too long or too short an inspiratory time.
Pathophysiology Related to Cardiac System

The shift of a patient from positive pressure ventilation to spontaneous
ventilation causes negative intrathoracic pressure leading to increase of
venous return, left ventricular afterload, and myocardial oxygen con
sumption. Thus, latent or unrecognized myocardial dysfunction may be
unmasked at the initiation of the weaning attempts. So, detailed cardiac
evaluation should be done in patient who fails ventilator weaning.
Cardiac evaluation generally requires 12 leads electrocardiogram (ECG),
echocardiography, cardiac enzymes, and coronary angiography. Manage
ment focuses optimization of cardiac function by after load and preload
reduction, inotropes, and antiarrhythmics.
Neuromuscular Abnormalities
In the absence of respiratory or cardiac pathology in the difficult-to-
wean patient, the contribution of neuromuscular abnormalities should
be considered. Pain anxiety, delirium, depressed central drive, and ICU
acquired weakness are all associated with weaning failure. Encephalitis,
brainstem hemorrhage/ischemia, metabolic alkalosis, and excessive
sedation can cause decrease in ventilatory drive even in the presence

of hypercarbia and hypoxia. Reversible cause of depressed central drive
should be identified and corrected; e.g. correction of metabolic alkalosis,
daily sedation holiday, etc. Critical illness neuromuscular abnormalities
(CINMA) are the most common peripheral neuromuscular disorders seen
in the critical care setting and commonly involve both muscles and nerves.
CINMA was a risk factor identified to prolong MV, weaning failure, and need
for tracheostomy in various observational studies.37 Emerging evidence has
observed benefits from early mobilization and physiotherapy.
Metabolic and Endocrine Abnormalities

Hypophosphatemia, hypomagnesemia, and hypokalemia are known
causes of muscle weakness. Hypothyroidism and hypoadrenalism may
also contribute to difficulty in weaning.3 In the obese patients, decreased
respiratory compliance, high closing volume/functional residual capacity
ratio, and increased work of breathing might be expected to affect the
duration of MV. However, a study that looked at the effect of obesity on
duration of MV and length of ICU stay, found increased ICU stay but not
the duration of MV in this group of patients.38
Diet has been seen to affect the duration of MV in patients with chronic
respiratory failure. A study showed that a high fat, low carbohydrate enteral
feeding can decrease arterial carbon dioxide tension and duration of MV in
comparison to standard isocaloric enteral feeding.39
MANAGEMENT OF PROLONGED WEANING FAILURE

Despite correction of all possible reversible causes, a considerable number
of patients who receive MV experience prolonged weaning failure. These
patients require sizeable hospital resources for management.
Tracheostomy
Tracheostomy is a common intervention in patient with repeated weaning
failure and anticipated prolonged MV. It has various advantages including
smooth management of airway, improved patient comfort and communication,
decreased need for sedatives, improved respiratory mechanics facilitating
earlier weaning from respiratory support, earlier transition to oral feeding,
patient mobilization, and reduced oropharyngeal trauma.3,40
Rehabilitation
Ventilator-dependent patients in the ICU continue to have systemic
inflammation and catabolism along with limited mobility and suboptimal
nutrition. All these factors particularly affect the neuromuscular system.

Rehabilitation effort focuses on restoration of muscle power and endurance.
It acts as different forms of exercise through passive-active movements and
posture.
Specialized Weaning Unit

To take care of difficult-to-wean patients, different locations and modalities
of assistance have been established, e.g. respiratory intermediate intensive
care units (RIICUs) within acute care hospitals, home ventilation with
telemonitoring, etc.41
OTHER RELATED ISSUES

Non-invasive Ventilation in Weaning
Use of non-invasive ventilation (NIV) has been evaluated for three different
indications during weaning—(1) as an alternative weaning modality for
patients who did not tolerate the initial weaning trial, (2) as a treatment
option for patients who developed ARF within 48 h of extubation, and (3)
as a prophylactic measure after extubation for patients who are at high risk
for reintubation but who did not develop respiratory failure.4
In a multicenter trial in (37 centers in eight countries) 221 patients
who were electively extubated after a minimum of 48 hours of MV and
who developed respiratory failure within the subsequent 48 hours were
randomly allocated to be ventilated by NIV by face mask or standard
medical therapy. Rate of reintubation was 48% in both the groups but the
rate of death in the ICU was higher in the NIV group (25% vs 14%; relative
risk, 1.78; 95% confidence interval (CI), 1.03–3.20; P = 0.048). The median
time from respiratory failure to reintubation was longer in the NIV group
(12 hours vs 2 hours 30 minutes, P = 0.02). These results show that NIV
does not prevent the need for reintubation and may increase mortality in
patients who have respiratory failure after extubation, by possible delay in
reintubation.42
Another multicenter RCT compared tracheal reintubation among
patients with hypoxemic respiratory failure following abdominal surgery
with standard oxygen therapy or NIV delivered via facial mask among 293
patients. Reintubation occurred in 33.1% in the NIV group and in 45.5%
in the standard oxygen therapy group within 7 days after randomization
(absolute difference: −12.4%; 95% CI, −23.5% to −1.3%; P = 0.03).43
These results show that NIV should be considered in select group of
patients, especially those with hypercapnic respiratory failure, to shorten
the duration of intubation. It may be used with caution in those patients
with hypoxic respiratory failure, but, it should not be routinely used in event
of extubation failure.3
Role of High-flow Nasal Cannula

Role of high-flow nasal cannula may be promising in postextubation failure
particularly in hypoxic failure. A multicenter study evaluated the effect of
postextubation high-flow nasal cannula on the rate of reintubation after
extubation. Reintubation within 72 hours was less common in the high-flow
group (4.9% vs 12.2%) in comparison to the conventional groups [absolute
difference, 7.2% (95% CI, 2.5–12.2%); (P = 0.004)]. Postextubation respiratory
failure was less common in the high-flow group [8.3% vs 14.4%, absolute
difference 6.1% (95% CI, 0.7–11.6%); P = 0.03)]. Thus, among extubated
patients, the use of high-flow nasal cannula oxygen reduces the risk of
reintubation within 72 hours as compared to conventional oxygen therapy.44
Role of Corticosteroids for the Prevention and

Treatment of Postextubation Stridor in Neonates,
Children, and Adults
A Cochrane Review in 2009 showed that corticosteroids have not proven
effective to prevent (or treat) stridor after extubation in neonates or
children. Subgroup analysis showed that in adults with a high likelihood of
postextubation stridor, corticosteroids administration 12–24 hours prior to
extubation, and reduced the postextubation stridor.45
Role of Fluid Management

Increased extravascular pulmonary fluid may increase infectivity by
altering the alveolar bacterial clearance. Restrictive fluid therapy to prevent
fluid overload may, therefore, decrease incidence of VAP in intubated
patients.
Data from the B-type Natriuretic Peptide for the Fluid Management of
Weaning (BMW), RCT performed in nine ICUs across Europe and America
showed that more negative median (interquartile range) fluid balance
during weaning is associated with a shorter time to successful extubation.46
The incidence of VAP was significantly lower in B-type natriuretic peptide
(BNP) driven group (17.8% vs 9.2%).46
Thus, a depletive fluid management strategy initiated during the
weaning process has the potential for lowering VAP risk and ventilation
duration.
T-piece or PSV Breathing Trails for Patients with COPD

The concern of dynamic hyperinflation in patient with COPD may prompt
use of PSV during SBT instead of T-piece. A recent study on 190 patients
with COPD, who had at least 48 hours of invasive MV support and were
considered able to undergo an SBT, were randomized to 30 minutes of
T-piece trial or PSV at 10 cm H2O. All patients were pre-emptively connected
to NIV after extubation. It was found that extubation at first SBT was
achieved in 78% of patients. The mean duration of MV was 10.82 ± 9.1 days
for the T-piece group and 7.31 ± 4.9 days for the PSV group (P < 0.001). The
time to liberation was 8.36 ± 11.04 days for the T-piece group and 4.06 ±
4.94 for the PSV group [univariate mean ratio = 2.06 (1.29 ± 3.27), P = 0.003]
for the subgroup of patients with difficult or prolonged weaning. PSV and
SBT may be considered a reasonable strategy for COPD patients, although
further studies are required to corroborate this hypothesis.47
CONCLUSION
Liberation from MV in ICU patients often appears to be a blend of art and
science. Although weaning form invasive MV is one of the best studied areas
in intensive care medicine, there are still questions relating to predictive
models of weaning, newer weaning modes, the role of tracheostomy, and
use of ultrasound, echocardiography, and biomarkers. Weaning from MV
remains an evolving domain of intensive care where more research is
required to clarify unsettled terrains.
KEY POINTS
• Timely liberation from MV is crucial to prevent ventilator-associated
pneumonia, neuromuscular weakness, prolonged ICU, and hospital stay.
• Weaning readiness should be assessed with various weaning parameters
and indices.
• Abrupt discontinuation of ventilation, SBT, ASV, SmartCareTM, and
proportional assist ventilation are acceptable methods of weaning.
• Weaning failure needs systemic assessment and correction of underlying
pathophysiology.
• Prolonged MV many a times needs specialized weaning units, e.g. RIICUs
within acute care hospitals. Home ventilation with telemonitoring may be
a modality for the future.
• Non-invasive ventilation and high-flow nasal cannula have been studied
to manage weaning failure that yielded mixed results.
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2018;13(8):e0202404.
CHAPTER
13 Intraoperative Thermoregulation
Ashu Sara Mathai, Anita Mathew
INTRODUCTION
Thermoregulation is the mechanism by which the hypothalamus regulates
the human body temperature at a stable level, normally between 36.5°C and
37.5°C.1 However in the intraoperative period, temperature regulation may
be altered by a variety of factors such as, anesthesia, use of intravenous (IV)
fluids, cold ambient temperature, exposure of the underlying tissues during
surgery, use of cold irrigating fluids, etc.
Despite widespread international agreement regarding the benefits
of maintaining perioperative normothermia, a very large percentage of
surgical patients still experience inadvertent perioperative hypothermia
(IPH). There is still a large gap among healthcare providers between
knowledge of the problem and use of active measures to circumvent it. A
questionnaire study evaluating the attitudes of anesthesiology specialists in
Turkey toward monitoring perioperative temperature revealed that only 26%
of physicians routinely monitored patients temperature intraoperatively
(predominantly in the newborn population) and used the skin/axilla
as the most preferred monitoring site. This, despite most of them being
aware of the risks of hypothermia and its complications.2 In a large survey
of 8,083 surgical procedures across 316 hospitals in Europe, it was found
that patient temperature was monitored in only 19.4% patients [25% during
general anesthesia (GA) and 6% during regional anesthesia (RA)] of which
only 43% of the former patients were actively warmed as compared to a
mere 28% of the patients in the latter group.3 The reasons for this lacuna
could vary from failure to recognize the risk of hypothermia in all subsets
of patients undergoing surgery, failure to accurately estimate the core body
temperature, failure to anticipate decreased core temperature following
anesthetic induction, and a mistaken assumption that the perioperative
core temperature is relatively unimportant and easily correctable with warm
blankets.
This chapter aims to give an overview of the mechanisms underlying
normal thermoregulation in humans with a brief discussion of the factors
impeding temperature control under anesthesia. We will also explore some
Intraoperative Thermoregulation 191
of the consequences of IPH and study some of the current recommendations

and guidelines for its management.
MECHANISMS UNDERLYING THERMOREGULATION

Thermoregulation in the normal human body is closely regulated and
maintained within a tight range on the basis of multiple signals from
almost every type of tissue in the human body. “Threshold temperature”
is the temperature beyond which a response is triggered by the body,
and temperature control is tightly regulated by the body to within 0.2°C
(known as the interthreshold range). Different type of tissues and structures
send thermal signals to the hypothalamus, and thermal information is
preprocessed from the peripheral to central tissues.4 While heat gain is
primarily a result of metabolism and involvement of muscle activity, heat
loss occurs by conduction, radiation, convection, and evaporation due
to perspiration through the skin. The thermoregulatory information is
processed in three phases: (1) afferent input, (2) central regulation, and
(3) efferent responses.5
1. Afferent thermal sensing: Thermoregulatory information is received from
thermally sensitive cells throughout the body. There are two types of
cells: (i) cold-sensitive and (ii) warm-sensitive cells. Cold signals travel
via Aδ nerve fibers and warm information by unmyelinated C fibers.
Temperature signals from the skin, spinal cord, deep abdominal/thoracic
tissue, and other parts of the brain coalesce mainly within the anterior
spinal cord and travel to the primary area of temperature regulation,
the hypothalamus.6,7 The hypothalamus, other parts of the brain, the
spinal cord, deep abdominal and thoracic tissues, and the skin surface
contribute roughly to around 20% of the thermal input to the central
regulatory system.
2. Central regulation: Central regulation is integrated by hypothalamus,
however, most thermal information is preprocessed in the spinal cord
and other parts of central nervous system. Detection of threshold
temperature by the body is unknown but the proposed mechanism
is mediated by dopamine, norepinephrine, 5-hydroxytryptamine
acetylcholine, neuropeptides, and prostaglandin E1. The threshold
varies in both sexes (circadian rhythm) and monthly in women. It is
also affected by exercise, food intake, thyroid disorders, anesthetics,
and other drugs including alcohol, sedatives and nicotine and cold and
warm adaptation.5
3. Efferent responses: Effectors determine the ambient temperature range
that the body will tolerate while maintaining a normal core temperature.
This includes behavioral compensation (dressing appropriately,
modifying environmental temperature, assuming positions that minimize
skin exposure, and voluntary movements) and autonomic regulation

(cutaneous vasoconstriction, nonshivering thermogenesis which
increases metabolic heat production without producing mechanical
work and can double heat production in infants), shivering which
increases metabolic heat production by 50–100% in adults, and sweating.
MONITORING OF BODY TEMPERATURE

Temperatures vary within the body. The core compartment (consisting of
body tissues and organs that are located deep inside the body) comprises
highly perfused tissues whose temperature is high and uniform, compared
to the rest of the body. Organs such as the brain, heart, and liver, which
are highly vascular and have high basal metabolic rate, contribute primarily
to the core body temperature. This is approximately 2–4°C higher than the
peripheries (arms and legs). Core temperature is usually measured from
four sites: (a) distal part of esophagus, (b) pulmonary artery, (c) tympanic
membrane, and (d) nasopharynx. Other sites such as axillary, oral, bladder
(especially when urine flow is adequate), and rectal temperatures may be
used as surrogate sites for measuring core body temperature.5 When the core
body temperature increases, cutaneous blood circulation is increased which,
therefore, increases the shell temperature. Thermistors and thermocouples
are used to measure core body temperature because of their accuracy
(±0.5°C), low cost, and reliability.5 Mercury-in-glass thermometers are no
longer recommended as they are slow and cumbersome.
CAUSES OF THERMAL DYSREGULATION IN THE

PERIOPERATIVE PERIOD
General Factors in the Operating Room
In the operating room, heat loss may occur by radiation, conduction,
convection, and by evaporation.5 Radiation is the transfer of heat from the
body to the surroundings. Heat loss by conduction occurs when the body
comes in contact with cold objects such as metallic IV stands, operating
room table, etc. and transfers heat. The process by which heat transfer occurs
from the movement of surrounding airflow is known as convection. In the
operating room, cold laminar airflow over the body causes convective heat
loss. When body organs are exposed during surgery to the open atmosphere,
heat loss may additionally occur through evaporation. Evaporation of body
fluids and sweat and use of cold cleansing solutions cause additional heat
losses.8 Of these four mechanisms, the first (i.e. radiation) is the most
prominent cause of heat loss in the operating room.6
General Anesthesia
All general anesthetics impair normal autonomic thermoregulatory control
in that the cold response thresholds is markedly reduced, and the warm
response threshold is slightly elevated.5 The thermoregulatory response by
sweating remains intact during GA, although it may now be triggered only
at slightly higher thresholds.5
It has been found that under GA, the interthreshold temperature
range increases from 0.2–0.3°C to 2–4°C.9 Anesthetic agents like alfentanil,
propofol, dexmedetomidine, and inhalation agents like isoflurane and
desflurane mildly increase the sweating threshold,10-14 while other agents like
propofol and volatile anesthetics contribute to intraoperative hypothermia
by inhibiting the nonshivering thermogenesis.15 In children, it is found
that thermoregulatory vasoconstriction is impaired when halothane and
isoflurane are used.16,17 This, along with lack of behavioral regulation under
anesthesia make the patients more vulnerable to intraoperative hypothermia.
Recent studies have contributed to a greater understanding of the
importance of the core-to-peripheral temperature gradient in the human
body. The uneven body heat distribution accounts for the drop in the core
temperature in almost half of the body during the initial phase of GA,
whereas the rest of the body is 2–4°C cooler as compared to core. There
is vasodilatation after induction of anesthesia which causes redistribution
of body heat to the periphery from the central compartment.18 Radiation
and convection play a major role in this heat loss which is almost 90% as
compared to conduction and evaporation.7 During the first hour under GA,
80% of the drop in core temperature contributes to the redistribution of body
heat, which continues for at least 3 hours.19 Hypothermia is further aggravated
by heat loss from exposed skin surface, inhalation of nonhumidified gases
and use of cold antiseptic skin cleansing solutions.20,21 Approximately after 3
hours, if anesthesia continues, the core temperature hypothermia begins to
plateau followed by a counteractive autonomic peripheral vasoconstriction.
This restores the drop in core temperature and is known as the plateau phase.7
Neuraxial Anesthesia
Epidural and spinal anesthesia block neuronal impulses (both afferent and
efferent) to the lower body. These impair the thermoregulatory control via
three mechanisms:
1. Thermal discomfort is not provoked as expected and patients receiving
regional anesthesia do not feel cold despite becoming hypothermic.21
Though the mechanism responsible for this effect is not very well
understood, it is supposed that the absence of cold signals from the
lower part of the body is interpreted by the controlling center as relative
warmth.
2. There is reduction in the shivering threshold as well as vasoconstriction

by the central effects of neuraxial blockade which results in widening
of interthreshold range. This effect is directly proportional to the level
of neuraxial block, i.e. more the level of neuraxial block, greater the
impairment of thermoregulation.21 However, this effect is less than that
caused by general anesthesia.
3. All autonomic thermoregulatory defenses are primarily mediated
neurally. In neuraxial anesthesia, there is blockade of all pain signals
(afferent and efferent). Therefore, the effect of efferent signals controlling
vasoconstriction and shivering is impaired thereby affecting temperature
gain and maximum intensity.
EXTENT OF THE PROBLEM

Inadvertent perioperative hypothermia is said to occur when the core body
temperature accidentally reduces below 36°C during the period from 1 hour
before anesthesia until the first 24 hours in the postoperative period. This
is in contrast to therapeutic hypothermia used in certain neurosurgical and
vascular surgeries and following cardiac arrest in the intensive care unit
(ICU) and is deliberately induced for its beneficial effects.
The incidence of IPH reported worldwide is highly varied and ranges
between 4% and 72%.22 A single-center study in Ethiopia reported that the
incidence of postoperative hypothermia was 30.72%. They concluded that
patients operated under GA were particularly vulnerable to postoperative
hypothermia and those with higher ASA statuses were more likely to
develop complications from postoperative hypothermia.23 In a national
study reported from China, the incidence of IPH was found to be as high as
44.3% with only 14.2% of patients being actively warmed intraoperatively.24
Patients developing hypothermia are at a higher risk for ICU admissions,
longer stay in the postoperative care area as well as in the hospital.24 The
incidence of IPH in India is largely unknown with no published data except
isolated case reports.
CONSEQUENCES OF INADVERTENT
PERIOPERATIVE HYPOTHERMIA
Inadvertent perioperative hypothermia can lead to serious cardiovascular,
hemorrhagic, and infectious complications. This is particularly a serious
concern among patients belonging to the older age group and those with
multiple comorbidities. These vulnerable patient groups are not only more
likely to develop hypothermia but are also at a higher risk of its attendant
complications.
The most prominent complication associated with IPH is an increased
bleeding risk from an impaired functioning of the coagulation cascade and
abnormal platelet aggregation. In vitro studies seem to suggest that while

mild hypothermia (up to 35°C) is relatively harmless, moderate and severe
hypothermia could progressively affect the functioning of the coagulation
cascade as well as the synthesis and activation of clotting factors.25 This is
especially aggravated when there is coexisting acidosis. In a large series
of 58,814 adults undergoing surgery of more than 1-hour duration where
more than 60% patients developed hypothermia shortly after anesthetic
induction, IPH was found to be independently associated with an increased
need for blood transfusions and a prolonged duration of hospital stay.26
In another study, hypothermia was reported to result in a 20% increase in
allogenic transfusion due to the increased blood loss.27
Inadvertent perioperative hypothermia is also associated with increased
risk of wound infections, delayed wound healing with tripling of reported
surgical site infections (SSIs) rates and prolonged hospital stay.28 This
is attributed to tissue hypoxia due to hypothermia-induced peripheral
vasoconstriction, impaired leukocyte activity, and decreased white blood
cell (WBC) movement toward the wound sites and poor scar formation. IPH
has also been reported to be strongly associated with the risk of developing
pneumonia and sepsis.29
Cardiac complications have also been reported to follow IPH, especially
in the postoperative period. This may be related to the increased risk of
hypothermia related arrhythmias, increased sympathetic stress response,
increased catecholamine levels, and postoperative shivering which increases
stress and myocardial oxygen demand in the postoperative period.30 In
patients with ischemic heart disease undergoing major vascular surgery,
the occurrence of hypothermia could potentially increase the risk of
postoperative cardiac events.31
Other complications resulting from IPH have also been reported. In a
retrospective study reported from India on patients undergoing scoliosis
surgery, the occurrence of hypothermia was correlated with need for
postoperative mechanical ventilation and the authors concluded that
implementation of measures to prevent hypothermia is essential in such
major surgeries.32 A recent study on 124 patients undergoing radical
cystectomy for bladder cancer implied that development of hypothermia
intraoperatively resulted in higher chances of cancer recurrence and poor
survival rates.33 Other reported complications resulting from postoperative
shivering secondary to IPH include patient discomfort and distress,
increased cerebrospinal fluid (CSF) and intraocular pressures, and wound
pain from muscular contractions.34
The occurrence of IPH not only contributes to an increased patient
morbidity and mortality but can also impose significant hospitalization
costs on patients. Even mild intraoperative hypothermia (up to 1.5°C
below normal) can add 2,500–7,000 USD to the overall hospital costs per
surgical patient.35 Costs attributable to IPH result from a prolonged length

of recovery room stay as well as ICU and hospital stay, greater need for
blood and blood product transfusions, increased need for postoperative
mechanical ventilation and increased costs from other investigations and
procedures.36,37
MANAGEMENT OF INTRAOPERATIVE HYPOTHERMIA

The timing of initiation of patient warming as well as the type of warming
modality used greatly influences the efficiency of normothermia attained.
When warming is initiated in the preoperative period and carried over into
the intraoperative period, the core temperature is found to be more optimally
maintained than in nonwarmed patients and this difference is observed as
early as 30 minutes after induction of anesthesia. Warmed patients also have
a significantly lower incidence of hypothermia at the end of anesthesia. On
the other hand, warming initiated in the intraoperative or the postoperative
period takes much longer to achieve desired core temperature levels
(90–120 min and 2–3 hours, respectively).34 Thus, prevention is key to the
management of IPH and requires the concerted efforts of all healthcare
givers, especially the anesthesiology team, surgeons, perioperative and
postoperative nurses as well as the ICU staff. In a retrospective analysis of
7,786 German patients from January 2015 to December 2016, it was found
that patients who were prewarmed for 30 minutes or longer, before receiving
GA had significantly lower rates of intraoperative as well as postoperative
hypothermia as compared to patients who did not receive prewarming (P
< 0.0001).38
The National Institute for Health and Clinical Evidence (NICE) guidelines
make the following recommendations to prevent IPH.39
Preoperative Phase
• Preoperative assessment must include a risk assessment for potential
IPH. Patients with more than two of the following risk factors must be
closely monitored for the same:
▪▪ American Society of Anesthesiologists (ASA) grade II to V (hypothermia
risk increases as the ASA risk classification scores increase).
▪▪ A preoperative temperature below 36.0°C (especially when the clinical
condition of the patient preempts preoperative warming).
▪▪ Patients undergoing combined general and regional anesthesia.
▪▪ Patients undergoing intermediate to major vascular surgery and are
at a greater risk of cardiovascular adverse events.
• Prior to shifting to the operating room, the body temperature must
be measured, and, if the patient’s temperature is below 36.0°C, active
warming should be initiated. It is recommended that even if the patient’s

temperature is >36.0°C but below normal (37°C), active warming should
be provided for at least 30 minutes prior to initiation of anesthesia
(unless there is need for emergency surgery).
• On transfer to the operating room, active warming is to be continued.
Wherever possible, patients may be encouraged to walk into the theater
complex.
Intraoperative Phase
• Body temperature should be recorded before, during and at every half
an hour intervals after the induction of anesthesia.
• Ideally, anesthesia should be delayed if the patient’s temperature is
below 36.0°C (unless the clinical condition of the patient warrants an
urgent surgery).
• The ambient temperature in the operating room should be at least 21°C
while the patient is exposed. Once the patient has been adequately and
actively warmed, the room temperature may be reduced to allow better
working conditions for the surgeons. The NICE guidelines recommend
that if the ambient temperature is too uncomfortable for the operating
surgeons, cooling equipment may be additionally considered for them.
• Wherever possible, the patient’s body should be well covered and the
drapes uncovered only at the time of the surgical preparation. This
ensures that heat is conserved and radiation and conductive heat losses
are minimized.
• All intravenous fluid bottles/blood products/other irrigating fluids
should be warmed to 37°C before use.
• In all surgeries where the duration of anesthesia is likely to be more than
half an hour, active forced-air warmers should be used. In patients with
high risk of IPH, warmers should be employed even when the surgical
duration is less.
Postoperative Phase
Postoperatively up to 24 hours after entering the recovery area, monitoring
of all postoperative patients must include temperature monitoring
commencing from the time the patient enters the recovery room followed
by measurements at 15-minute intervals. Prompt corrective measures must
be employed if the patient’s temperature falls below 36.0°C, including
the use of blankets, forced air warmers, and warm IV fluids. Patients
may be transferred to the ward only when body temperatures reach more
than 36°C.
METHODS OF WARMING
Some of the methods currently being used in the management of hypo
thermia include the following:
Active Warming Mechanisms

• Forced-air blankets: These are one of the most effective and commonly
used means of warming patients and work on the principles of convection
and radiation. They are convenient to use and ideal in the preoperative
and intraoperative periods to prevent IPH. The patient is attached to
a portable heater which blows warm air through a flexible hose into a
receptacle, usually a two-layer blanket, which is spread over the patient’s
body. The forced air creates a warm air-filled layer over the body and
heat transfer results from the movement of warm air across the surface
of the patient’s skin. While the benefit of using forced air warmers for
patients under GA has been well established,40 it has been shown that
even patients undergoing surgery under neuraxial block benefit well
from warming with forced air warmers. A recent systematic review of
1,587 case records included in randomized controlled trials studying the
efficacy of warming devices (active vs passive) in patients undergoing
surgery under neuraxial block indicated that the former is more efficient
in preventing perioperative hypothermia.41
• Electric blanket
• Water mattress
• Radiant heating
• Warmed blankets
• Heating gel pad
• Humidification and warming of inspired gases: Cold and dry anesthetic
gases may potentially cause heat loss in patients receiving general
anesthesia. However, as recent studies indicate, this may not be as
significant as earlier believed. It is found that very less heat is actually
lost via respiration and airway heating/humidification does not increase
the core body temperature significantly.42 Hence, heated circuits are not
used routinely in contemporary clinical practice.
• Warm IV fluids: It has been well recognized that cold intravenous and
irrigating fluids significantly reduce the core body temperature. Many
fluid warming methods have been studied and employed for the same
including, use of water baths, counter-current heat exchange, use of
microwave radiations to heat fluids, and conductive warming of fluids.
Warm fluids, especially when used in conjunction with forced-air
warming devices, aid in the maintenance of normothermia. A large
Cochrane database review of 24 studies (1,250 participants) comparing
different methods of warming IV fluids reported that patients receiving
warmed IV fluids (41°C) had a warmer core body temperature (at
least 0.5°C more) perioperatively than their counterparts who received

IV fluids at room temperature (37°C). The former patients also had a
reduced incidence of shivering postoperatively.43
• Unclear evidence: (a) Role of pharmacologic vasoconstriction with use
of ketamine, atropine, phenylephrine, and (b) use of IV nutrients to
counteract hypothermia. More research is needed in these areas.
Thermal Insulation Mechanisms

• Reflective blanket
• Reflective clothing.
The use of warming devices is not without risk, however, especially
when they are used without proper precautions. The closed claims project
database of the ASA,44 found that burns and infections topped the list
of reported complications, and this was particularly more in patients
undergoing long surgeries. The combination of heat and pressure applied
by the warming devices, especially over bony prominences resulted in the
majority of these injuries. By 2004, the total claims in the same database had
raised to 6,449 of which, 145 were burned injuries, with the majority of these
caused by heated material followed by air warming devices.45 There have
been some concerns that forced-air warmers could potentially increase
the risk of infections by disrupting the laminar airflow in the operation
theater, by harboring microorganisms on their surfaces, and in instances
when warming blankets have been reused.46 However, most of these can
be minimized by the correct and proper use of these devices.47
Despite all the evidence regarding the benefits of preventing intra-
operative hypothermia, in the real world scenario, ideal temperature
targets are hard to achieve and remains a challenge for most perioperative
physicians. The results of a 6-month intervention among 3,228 patients to
prevent perioperative hypothermia in clinical practice revealed it is difficult
to abolish intraoperative hypothermia completely. Even with prewarming and
continuous intraoperative warming, hypothermia occurred in close to 32%
patients during the intraoperative period and close to 19% postoperatively. The
patients who received prewarming prior to surgery, however, fared significantly
better than patients who only received intraoperative warming, with the latter
being at a 1.8 times greater risk for hypothermia than the former.48
CONCLUSION
Despite clear and well-researched data regarding the consequences, both
in terms of poor patient outcomes as well as increased costs associated
with IPH, it continues to be an under-recognized and neglected problem
in most operating rooms. It is to be understood that all forms of anesthesia,
including, general, regional or field block can contribute to hypothermia.
Unless well-planned, concrete and proactive measures are implemented, the

risk of developing IPH and its attendant complications are high, especially
in vulnerable patients at the extremes of age and patients with higher
ASA risk classifications. All perioperative healthcare workers, especially
anesthesiologists, surgeons, perioperative and postoperative nurses, and
critical care nurses, need to have a thorough understanding of the need
for monitoring for IPH, the risk factors contributing to increased patient
vulnerability, management of some of the adverse outcomes following
IPH and the ways to prevent and treat this all too common intraoperative
complication. All personnel must work toward promoting normothermia,
not only in the intraoperative period but more importantly as a continuous
goal during the entire perioperative period. This is key to increasing patient
safety, patient satisfaction, and improving overall patient outcomes.
KEY POINTS
• Inadvertent perioperative hypothermia continues to remain an under-
recognized complication in most operating rooms.
• Both general and regional anesthesia may cause IPH.
• Prevention is key to management and begins with warming in the
preoperative phase itself.
• Effective maintenance of normothermia in the perioperative period not only
reduces the risk of major complications like increased bleeding, cardiac
complications, and shivering but also significantly brings down the costs
of hospitalization and improves patient satisfaction.
• Data from India is lacking in this regard. Young researchers are encouraged
to explore lacunae in this area, especially innovation of cost-effective
warming devices in the operating room for use in developing countries.
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accessed August, 2019].
40. Ouellette RG. Comparison of four intraoperative warming devices. AANA J.
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41. Shaw CA, Steelman VM, DeBerg J, et al. Effectiveness of active and passive
warming for the prevention of inadvertent hypothermia in patients receiving
neuraxial anesthesia: a systematic review and meta-analysis of randomized
controlled trials. J Clin Anesth. 2017;38:93-104.
42. Hynson JM, Sessler DI. Intraoperative warming therapies: a comparison of
three devices. J Clin Anesth. 1992;4:194-9.
43. Campbell G, Alderson P, Smith AF, et al. Warming of intravenous and irrigation
fluids for preventing inadvertent perioperative hypothermia. Cochrane
Database Syst Rev. 2015;13:CD009891.
44. Cheney FW, Posner KL, Caplan RA, et al. Burns from warming devices in
anesthesia: a closed claims analysis. Anesthesiology. 1994;80:810.
45. Kressin KA. Burn injury in the operating room: a closed claims analysis. ASA
Newsl. 2004;68:9-11.
46. Sigg DC, Houlton AJ, Iaizzo PA. The potential for increased risk of infection
due to the reuse of convective air-warming/cooling coverlets. Acta Anaesthesiol
Scand. 1999;43:173-6.
47. John M, Ford J, Harper M. Perioperative warming devices: performance and
clinical application. Anaesthesia. 2014;69:623-38.
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month period in clinical practice. Anaesthesist. 2016;65:423-9.
Platelet-rich Plasma for Management of Chronic Pain... 203
CHAPTER
14 Platelet-rich Plasma for

Management of Chronic Pain
and Degenerative Conditions: A
Critical Review of Evidence
Babita Ghai, Nitika Goel
INTRODUCTION
The administration of platelet-rich plasma (PRP) is increasing in recent
past in the field of chronic pain management, orthopedics, and sports
medicine for its alleged regenerative ability.1,2 Several studies have found
the beneficial effects in clinical outcome after injecting PRP, however, many
others report little or no clinical benefits. PRP has been studied for various
degenerative diseases such as osteoarthritis (OA) knee, intervertebral disk
(IVD) degeneration and multitudes of ligamental injuries. In OA knee, a high
number of studies demonstrate better outcomes with PRP injections while
others report to the contrary. Its use to treat ligament, tendon, and skeletal
muscle injuries have also shown conflicting results. Current evidence of
PRP effectiveness in the management of skeletal tissue injury remains
inconclusive. For chronic pain management, similar contrary results were
reported ranging from no or little pain relief to reduction in pain.3 Numerous
variables have been found which increase or decrease the analgesic
efficacy of PRP. Therefore, in none of the conditions, strong evidence in
improvement of symptoms has been found. This is most probably due to
lack of standardization of PRP preparation, underpowered studies, dearth
of high-quality randomized trials, inclusion of too many variables, and poor
patient stratification.3
WHAT IS PLATELET-RICH PLASMA?

Platelet-rich plasma is centrifuged autologous blood concentrate containing
3–6 times higher than normal concentration of platelets.4 To prepare PRP,
the patient’s blood is drawn and then this autologous blood is centrifuged.
Based on relative density, various components of blood separate allowing
separation of platelet-poor plasma from other components.5 Further
centrifugation leads to separation of buffy coat layer containing PRP and
or leukocytes. There are abundant devices being used for the preparation
of PRP and PRP composition differs largely depending on the device being
used. Different devices yield platelet concentrates ranging from 1.99 to 9.3-
folds above baseline.3 There are various formulations of PRP available which
differ in terms of platelet concentration, cell content, method of activation,
and many other features. This heterogenicity in preparation is considered
as one of the major limiting factors for its clinical use and may lead to
its reduced applications.3 Also, the optimal platelet concentration inducing
benefit is still unknown.
TYPES OF PLATELET-RICH PLASMA

Various classifications of PRP are described in literature due to lack of
standardization of PRP preparation. PRP can either be in activated form
or nonactivated form and can be either leukocyte-poor or leukocyte-rich.
Mishra et al. classified PRP into four types depending on leukocyte content
and state of activation.6 For activation form, PRP is prepared with calcium
chloride with or without thrombin.6-8 The activation results in the release
of granules from platelets and hence are proposed to be in abundance
upon injection.8 While nonactivated form is proposed to get activated with
intrinsic collagen and thromboplastin within the connective tissue.8
Another type of PRP classification is as leukocyte-poor and leukocyte-
rich. The role of leukocyte in PRP is not very clear. It is projected to play a
role in inhibiting bacterial growth and promote wound healing. However,
it is also proposed to exaggerate inflammatory response by stimulating
inflammatory cytokines and may stimulate the release of reactive oxygen
species.8
Platelet-rich plasma has also been classified extensively by various other
authors.9,10
PROPOSED MECHANISM OF PLATELET-RICH PLASMA?

Though the exact mechanism as of how PRP works is still unknown, there are
various postulated mechanisms. It is hypothesized that platelet concentrate
increases the secretion of growth factors, hence theoretically improving
the healing process.4,5,11 Another proposed mechanism is that this platelet
concentrate may promote mitogenesis of capable healing cells.7 Few of the
growth factors proposed to be present in PRP are platelet-derived growth
factor (PDGF), vascular endothelial growth factor (VEGF), epithelial growth
factor (EGF), and transforming growth factor-beta (RGF-b). Additionally, it
is postulated that PRP may promote bone formation containing adhesion
molecules such as fibrin, fibronectin, and vitronectin.4
DOES PROPOSED MECHANISM OF PLATELET-RICH

PLASMA WORK IN VIVO?
In vitro studies have reported an increased amount of growth factors in
PRP.12 However, this finding has not been replicated in vivo studies in terms
of better patient outcome and improvement in healing.13 In clinical practice,
the role of PRP to enable the growth factors and proteins to promote healing
and regeneration is still in a very preliminary state with a very low scientific
level of evidence.14,15
CLINICAL EVIDENCE OF PLATELET-RICH PLASMA IN

OSTEOARTHRITIS KNEE
Osteoarthritis knee is reported with an incidence of 10–15% in patients aged
60 years and above and is considered among the most common degenerative
disorders in elderly.16-18 There is a gradual progression of disease due to
limited regeneration capability of articular cartilage.16 Treatment of OA
knee includes nonsurgical and surgical modalities. Although the definitive
treatment is surgical, nonsurgical treatment has gained popularity in the
initial stages of the disease and includes administration of nonsteroidal anti-
inflammatory drugs (NSAIDs), intraarticular injection of steroids, genicular
nerve blocks, and more recently, injection of PRP.18
Role of PRP is most extensively studied in OA knee. Extensive data is
available for the use of PRP for OA knee, but the present literature discloses
contradictory evidence. A recent systematic review has reported no long-
term benefit in patient primary and secondary outcomes in patients with OA
knee or after total knee replacement (TKR).19 Although PRP demonstrated
effectiveness, it was for short- to medium-term pain control only. In
another meta-analysis comparing intra-articular hyaluronic acid (IAHA)
versus intraarticular PRP (IAPRP), the author concluded that IAPRP was
no way superior to IAHA.20 In another systematic review and meta-analysis
including five RCT and five nonrandomized trials, authors demonstrated
that PRP reduced pain score with functional improvement at 6-month
follow-up.21 Similar findings at 12 months were reported in comparison to
HA alone, though significant effects were not found at 6 months.22 Shen et
al., reported significant improvement in WOMAC scores at 3 and 6-month
follow-up.18 However, it is pertinent to note that both these meta-analysis
reported significant diversity in the outcome.18,22
Limitations for Platelet-rich Plasma Studies for

Osteoarthritis Knee
Many authors while examining the data in systematic reviews and meta-
analysis have pointed out large heterogenicity in PRP preparation and in
methodology. The major variable, which is accounted for this heterogeneity,

is PRP composition due to variable PRP processing devices and technique.
This heterogenicity in preparation is considered as one of the major limiting
factors for its clinical use and may lead to its reduced applications.3 Also,
the optimal platelet concentration inducing benefit is still unknown.23
Most studies reporting positive outcome usually report minimizing
symptoms, that is, decline in pain without much benefit to disability and
usually do not have long-term follow-up. Studies with follow-up to 12
months report decline in pain relief with passage of time. Other limitations
are underpowered studies, the dearth of high-quality randomized trials, and
the inclusion of too many variables and poor patient stratification.
Summary of Evidence about the Role of Platelet-rich

Plasma in Osteoarthritis Knee
There is a low level of evidence to support the application of PRP in OA
knee for improvement in patient-reported outcome. Evidence reveals that
PRP probably exhibits better outcome in younger patients with less severe
grading of OA knee. More high-quality randomized controlled research
needs to be done on the effectiveness of PRP with each KL grade of OA.
With current evidence, it is obvious that PRP is not as efficacious for pain
control and functional improvement in advance OA knee and cartilage
degeneration.23
Hence, when looking at the evidence, current guidelines from National
Institute for Health Care Excellence (NICE), UK and American Academy of
Orthopaedic Surgeons (AAOS) suggest that the evidence is inconclusive for
the use of PRP for OA knee.24
Recommendations for Further Research for the Role of

Platelet-rich Plasma in Osteoarthritis Knee
High-quality future studies in need to be conducted with adequate power
including optimization and standardization of PRP preparation in each
grade of OA knee with long-term follow-up. Studies delineating and
proving in vivo mechanism of PRP are also needed. Moreover, optimization
of dosage, volume, frequency, and timing need to be evaluated.25 Before
widely implementing PRP for management of OA knee, all these concerns
should be attended to.14,26,27 The economical aspect and cost-effectiveness
also needs to be addressed.28
CLINICAL EVIDENCE OF PLATELET-RICH PLASMA IN

CHRONIC LOW BACK PAIN
Low back pain (LBP) is one of the most common health problems, affecting
80–85% of population over their entire lifetime. The point prevalence of
activity limiting LBP has been estimated to be around 12% while the 1-month
prevalence is 23%.29 Intervertebral disk degeneration is the most common
pathology in LBP. Disk degeneration involves circumferential tears in the
annulus fibrosus that progresses to a radial tear leading to disk herniation,
loss of disk height, and resorption.30 Because of decreased blood supply
of the IVD, tissues have very little capacity for self-repair. The therapeutic
effect of platelets is proposed to occur by approximating the torn edges
of degenerated disk, leading to healing of cells.30 Many in vitro studies
have shown PRP to have potential in stimulating cell proliferation and also
increase the metabolic activity of IVD cells.31,32 Akeda et al. reported PRP
having stronger effects in the annulus fibrosus region than in the nucleus
pulposus in the alginate cultured porcine IVD cells.31 Few in vivo studies
also report similar results as in vitro, showing the regenerative potential of
PRP on IVD.32,33 However, owing to negligible standardization in preparation
and activation of PRP, variation in results is expected.
In their first preclinical experimental study, Nagae et al. reported the
effectiveness of PRP-impregnated gelatin hydrogel microspheres (PRP-
GHMs) in minimizing the IVD degeneration. They demonstrated minimal
efficacy of PRP injections without microspheres. They suggested PRP-GHMs
that immobilized growth factors as a better therapeutic option compared to
PRP alone.33
Clinical Studies of Platelet-rich Plasma for

Low Back Pain Patients
Intradiskal Injection
Most of the evidence of PRP for intradiskal injection includes small
observational studies and case series34-36 with only one high-quality
randomized controlled trial.37
In their prospective observational study on 14 patients, Akeda et al.
reported a decrease in mean pain scores in 70% patients over 1-month
follow-up.34 In a case series of six patients, Navani et al. reported decreased
pain scores and improvement in mental and physical health at 6 months with
an intradiskal injection of PRP.35 In another observational trial of 22 patients,
Levi et al. documented a decrease of 50% in visual analog scale (VAS) and at
least 30% decrease in Oswestry Disability Index at 6-month follow-up.36
In the first randomized double-blind controlled trial of intradiskal
PRP therapy for discogenic LBP, performed by Tuakli-Wosornu et al., 58
participants were grouped into treatment or control groups in 2:1 ratio.37
The study group received intradiskal PRP injection while the control group
received a contrast injection after provocative discography. The study group
reported statistically significant improvements in numerical rating scale
(NRS) best pain, Functional Rating Index (FRI), and patient satisfaction
[North American Spine Society (NASS) outcome questionnaire], compared

to the control group at the 8-week follow-up. Moreover, the effect of PRP in
the study group was sustained for 2 years. The main limitation of this study
was the limited follow-up of the control group of just 8 weeks.37
Nonintradiskal Platelet-rich Plasma Injections

Other than intradiskal injections, facet joint and sacroiliac joint (SIJ) PRP
injections have also been used in LBP patients. Again, most of the literature
is of small case series, retrospective data and underpowered studies with
dearth of good quality randomized trial.
In a case series reported by Aufiero et al.,38 improvement in symptoms
was seen by more than 50% in five patients following PRP facet joint injection.
In a retrospective observational study performed by Kirchner and Anitua et
al.39,40 in 86 patients, intradiskal and intra-articular facet infiltrations of PRP
were performed. VAS scores declined significantly in 90% patients. Wu et al.
in an observational uncontrolled study performed a lumbar facet joint PRP
injection in 19 patients only. On 3-month follow-up, VAS, Roland-Morris
Disability Questionnaire (RDQ), and Oswestry Disability Index (ODI) scores
significantly improved.41 PRP when compared to corticosteroid injection in
46 patients randomized to two groups, showed significant analgesic effects
at all-time points during PRP injections, scores in corticosteroid group
reversed and worsened at the 2-month time point after injection, whereas
those of the PRP group steadily improved.42
Hence, from the above data, it is clear that the high-quality randomized
trial of facet joint PRP injection is lacking.
Hussein and Hussein43 studied the effect of intramuscular injection
of PRP on 108 LBP patients presenting with atrophied lumbar multifidus
muscle and monosegmental degenerated IVD. Patients were treated with
weekly injections for 6 weeks and thereafter followed-up for 24 months.
Significant improvement in NRS and ODI scores were reported by them
at 12 months. Moreover, the improvement was sustained till the 24-month
follow-up. Platelet-rich plasma was injected in a circumferential manner
subfascially into the lateral masses, facet joints, and the other posterior spine
areas. Significant improvement of VAS was noted by 77%.44 PRP suspended
in stromal vascular fraction (SVF) has been injected intradiskally in 15
patients. All patients reported significant improvements in VAS, present pain
intensity (PPI), and short-form McGill Pain Questionnaire (SF-MPQ), and
short-form 12-physical component summary.45
Sacroiliac Joint Injection

Injection of PRP into SIJ have been reported to decrease the intensity of LBP
due to the pathology of these joints.46,47 Singla et al. compared steroid SIJ
injection and PRP SIJ injection for LBP and found decrease in pain intensity
by 90% in PRP group as compared to steroid group (25%).47
Summary of Evidence of Platelet-rich Plasma for

Chronic Low Back Pain
Despite preclinical encouraging results and increasing clinical interest,
most of the evidence for PRP for management of chronic LBP remain
inconclusive due to small sample size, nonrandomized uncontrolled trials
and heterogenicity of studies.
Based on the available literature, the American Society of Interventional
Pain Physicians (ASIPP) Guidelines synthesized evidence for various LBP
pathologies. The level of evidence for lumbar disk injections and SIJ injections
of PRP has been level III as compared to lumbar facet joint injections of PRP
which is level IV.48 Currently, more high-quality randomized controlled trial
is required with proper standardization of PRP preparation and activation
techniques before embarking on PRP as definitive therapy for LBP.
CURRENT USE OF PLATELET-RICH PLASMA IN

MUSCULOSKELETAL TISSUES
Though in the United States of America, Food and Drug Administration (FDA)
approved the use of PRP with ligament grafting and the approximation of
bony matrices during reconstructive procedures, its use across many studies
to treat ligament, tendon, and skeletal muscle has shown conflicting results.
The current evidence for the effectiveness of PRP in treating sports injuries
is inconclusive, uncertain, and inconsistent.49
Literature reports numerous studies documenting ineffectiveness of PRP
in tendon injuries and muscle strain in terms of activity scores and pain
levels. It is concluded across various studies that PRP is no more effective
than a placebo injection or intensive rehabilitation.50-54 A very recent cohort
study by Everhart et al. reported that PRP does not decrease the risk of
meniscal repair failure in the setting of anterior cruciate ligament (ACL)
that in the setting of concurrent ACL reconstruction.55
Another very recent randomized controlled trial (RCT) by Schwitzguébel
et al. concluded that PRP as compared to saline injection did not improve
clinical scores or tendon healing when injected within interstitial
supraspinatus tear but was associated with more adverse events.56
However, in a systemic review and meta-analysis, PRP has been known
to reduce pain in rotator cuff injuries and lateral epicondylitis.57 Between
all these conflicting reports, no concrete evidence exists regarding the
effectiveness of PRP in various sports injuries, again mainly due to indwelling
heterogeneity among them.
ADVERSE EVENTS WITH PLATELET-RICH PLASMA

Many authors highlighted the safety of PRP due to its autogenic nature; it
is not devoid of side effects/adverse event. Clear safety of PRP is difficult
to report, as most of the studies are not adequately powered to detect the
complication or adverse vent of PRP. A very recent case report of allergic
reaction to PRP in a 14-year-old boy has been reported when the PRP
was injected for treatment of bone cyst of distal tibia.58 An exuberant
inflammatory reaction has also been reported after one injection of PRP
used to treat jumpers knee in a 35-year-old male.59 Reports of dermatitis,
infection in existing ulcer, thrombophlebitis has been reported60 besides
increased thrombin time and activated thromboplastin time.61
These reports highlight that the safety of PRP is not clearly sure. The pure
autologous tissue may be safe but its preparation can considerably reduce
the safety.
CONCLUSION
Platelet-rich plasma is now being used with growing interest in the treatment
of almost all degenerative and tendinous injuries and for chronic pain
management. Though few studies have proved the effectiveness of PRP
in the treatment of LBP and OA knee, its superiority over other treatment
modalities in various conditions, still needs to be established. Furthermore,
defining details of pathologic condition, standardized PRP preparation,
ideal PRP concentration, frequency, and timing of injection need to be
investigated before its widespread use. The use of PRP based on current
evidence across different skeletomuscular injuries has been critiqued for
being inconsistent and uncertain.48 The studies showed marked variations in
number of PRP injections (single, multiple), initial blood volume withdrawn
for PRP isolation, volume of PRP injected (1–5 mL) and variable follow-up
periods ranging from 8 weeks to 18 months, thus leading to a lot of
heterogeneity in results.
To conclude, there are many questions open with regard to the basic
in vitro and in vivo biology of PRP, advantages and disadvantages and its
most applicable indication especially with respect to other management
approaches. Due to huge variability, the comparative analyses of current
evidence does not provide sufficient conclusion for PRP as an analgesic.
Hence, more high-quality trials are required to offer clear indications for
the use of PRP.
KEY POINTS
• Platelet-rich plasma use has greatly increased in recent past, for the
management of chronic pain and degenerative musculoskeletal diseases.
• Despite encouraging basic, experimental and preclinical results, literature

reports conflicting and variable results.
• The heterogenicity in preparation of PRP is considered as one of the major
limiting factors for its clinical use and may lead to its reduced applications.
• Platelet-rich plasma is most widely studied for the management of
osteoarthritis knee and current guidelines advocate inconclusive evidence
of PRP for OA knee.
• For chronic low back pain, level of evidence for lumbar disk injections
and sacroiliac joint injections of PRP has been level III as compared to
lumbar facet joint injections of PRP which is level IV.
• For skeletomuscular injuries, current evidence across different studies is
not proven.
• Despite FDA approving its use with ligament grafting and the approximation
of bony matrices during reconstructive procedures, the use of PRP for
different injuries has been criticized for being uncertain and inconsistent.
• The safety of PRP is not proven. The pure autologous tissue may be safe
but its preparation can considerably reduce the safety.
• Due to huge heterogenicity of studies, small sample size and
nonrandomized uncontrolled trials, the current evidence does not provide
sufficient conclusion for PRP as an analgesic. Hence, more high-quality
trials are required to offer clear indications for the use of PRP.
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Postoperative Myocardial Injury: Causes and Management 215
CHAPTER
15 Postoperative Myocardial
Injury: Causes and
Management
Arun Maheshwari, Elvin Daniel
INTRODUCTION
Postoperative cardiac complications carry high mortality and morbidity.
All over the world, major adverse postoperative cardiac event occurs
in approximately 5–10 million patients,1-3 and about 1 million adults
succumbed to death within 1 month of noncardiac surgery.2 Postoperative
myocardial injury (PMI) is reported to occur in 1–17% in all varieties of
surgery with in-hospital mortality of 15–25%,1-3 being particularly high in
the first 30 days. Surgical stress can trigger cardiovascular events such as
ventricular arrhythmia and myocardial infarction (MI) in individuals at high
risk, leading to PMI which can be a contributor to mortality after noncardiac
surgery.4-6 Because the vast majority of PMIs are asymptomatic, it is usually
missed in the absence of systemic screening.
DEFINITION OF MYOCARDIAL INFARCTION: DOES

POSTOPERATIVE MYOCARDIAL INJURY FIT IN?
As per the third Global MI Task Force,7 MI constitutes myocardial ischemia,
accompanied by raised cardiac biomarkers along with any of the following:
• Ischemic angina pain or distress.
• Electrocardiogram (ECG) changes.
• New regional wall-motion abnormality.
• Coronary angiography (CAG) showing thrombus.
The third universal definition describes five types of MI,7 as follows:
Type 1: Atherosclerotic plaque rupture and intraluminal thrombus causing
spontaneous MI.
Type 2: Imbalance between myocardial oxygen demand or supply leading
to myocardial ischemia.
Type 3: Sudden cardiac mortality with cardiac ischemic symptoms of MI
and new ECG changes.
Type 4a: MI associated with percutaneous coronary intervention (PCI) with
ischemic symptoms and raised biomarkers.
Type 4b: MI due to stent thrombosis.

Type 5: MI associated with coronary artery bypass grafting surgery.
Current diagnostic criteria for MI may be inadequate as found in evolving
evidence. Latest advances in the biomarker assays have led to more accurate
diagnosis of PMI, better prediction of risk, and their prognostic value can
help to diagnose PMI more accurately.8-11 Recently introduced clinical
concept of myocardial injury after noncardiac surgery (MINS), defined
myocardial injury due to ischemia prognostically relevant occurring within
30 days after noncardiac surgery.8 The main focus of this definition of MINS
is prognostic relevance of a peak in the high-sensitivity cTnT (hs-cTnT)
assay. High-sensitivity cTnT assay allows the detection of very low levels
of cTnT. Overall diagnostic accuracy of suspected PMI is improved with
the help of this assay, and a negative result also carries a high negative
predictive value. This assay is really helpful not only in diagnosing PMI but
also predicting 30-day mortality.10,11
DOES POSTOPERATIVE MYOCARDIAL INJURY

ALWAYS MEAN MYOCARDIAL INFARCTION?
Indeed, a MI is observed in only 14–40% of the patients with PMI as per the
definition. In almost 30% of patients with PMI, obstructive coronary artery
disease (CAD) is absent.12-15 Hence, the potential relevance of noncardiac
triggers of PMI cannot be underestimated. This emphasizes the knowledge
of different causative factors of PMI in order to get a better outcome of
such patients.
PATHOPHYSIOLOGY
The pathophysiological mechanism of PMI is debated. The most sought
explanation is supply-demand mismatch due to tachycardia, hypertension,
hypotension, or coronary artery obstruction (Flowchart 1). However, the
scientific literature supporting this explanation is not strong. Approximately
half of the patients had plaque instability causing perioperative acute
coronary syndrome (ACS) in one angiographic study.16 In another study
where optical coherence tomography was used to identify coronary artery
pathology. Thrombus was identified as the main lesion in 13% of the
perioperative MI cases and 67% of the nonoperative cases.17 Apart from
PMI, proponents of the term MINS describe nonischemic etiology such as
pulmonary embolism, sepsis, or cardioversion.18
Postoperative myocardial injury is mainly because of type I or type II
myocardial ischemia.4,6,16 Vulnerable plaque rupture with acute coronary
thrombosis and influenced by hemodynamic fluctuations, inflammation,
hypercoagulability can lead to type I ischemia.2,19 Type II myocardial ischemia
Flowchart 1: Pathophysiology of perioperative myocardial injury.
(CAD: coronary artery disease; IL: interleukin: TNF: tumor necrosis factor).
is explained by oxygen supply-demand mismatch such as tachycardia, hyper

or hypotension, and anemia.2,19
Hitherto, PMI was mainly believed to occur in patients with CAD.
However, scientific studies have raised the question on this assumption.
In a study of 955 noncardiac surgery patients, 28% of MI was observed
in patients with absence of CAD.15 In another study of old patients, it
was found that obstructive CAD on postoperative cardiac computed
tomography angiography (CCTA) scan was seen in only 50% of the
patients with PMI.20 However, microvascular damage cannot be assessed
in CCTA. Microvascular injury can lead to PMI in patients with chronic
hypertension. Plaque instability leading to PMI cannot be excluded by the
absence of obstructive CAD. Even mild obstructive lesions can also lead to
type I myocardial ischemia.21 The fact that the absence of obstructive CAD
in 30–50% of patients with PMI suggests noncoronary causes like sepsis,
pulmonary embolism, and cardiac arrhythmias which play a significant role
in patients with PMI.14,22,23
DIAGNOSIS
Patients with PMI may not have classical ischemic pain due to pain
medications. Vascular Events in Noncardiac Surgery Patients Cohort
Evaluation (VISION) study 2017 demonstrated that up to 90% patients with
PMI experience no anginal symptoms,3,10 and half of such cases remain
unidentified.24
We must depend on clinical signs and available technological advances,
not symptoms, for timely detection of PMI. A study reported that only 14%
of such patients experience chest pain.1 Most common initial signs in such
scenario are the hypotension, diaphoresis, nausea, and low saturation, and
ECG changes.25
Hypotension
Prognostic clinical implications of intraoperative hypotension remain
questionable. However, it was found every minute with systolic blood
pressure below 80 mm Hg increases 1-year mortality by 3.6%.26 One study
also demonstrated that intraoperative hypotension and anemia can greatly
influence postoperative myocardial ischemic events.24,27
Electrocardiographic Changes
As per American College of Cardiology,24 ECG changes such as new Q-wave
changes, ST-segment elevation or depression in any two consecutive leads
can be used in diagnosing PMI.
VISION study found that postoperative ECG changes like ischemic
ST-segment changes and left bundle branch block along with troponin
elevation were found to be associated with 1-month mortality.9
Biomarkers
A near-absolute myocardial tissue-specific biomarker is troponin. However,
there are certain fallacies associated with its measurement. Major factor in
the recognition of PMI is believed to be peak troponin concentrations. It
has been found that noncardiac complications such as sepsis, respiratory
insufficiency, and bleeding were associated with a postoperative troponin
increase of over 100% compared to preoperative baseline measurements.
Conventionally, it is presumed that ischemic cardiac damages can cause
a major rise in postoperative troponin and noncardiac complications have
only a mild effect on the troponin.28,29 However, it should be also kept
in mind that noncardiac complication with cardiac implications such as
pulmonary embolism can also cause a significant elevation in troponin.
Pulmonary embolism is great stress on myocardium due to increased right
ventricular pressures, hypoxia, and hypotension.30,31 Troponin monitoring
can help us in recognizing not only MI but also other serious yet manageable
postoperative complications. Troponin elevations, therefore, still robustly
predict mortality.10,32,33 It is worthy to note that excessive importance on
myocardial ischemia may lead to failure of recognition of noncoronary
causes of PMI.
Raised TnT levels should be measured at 3 and 6 hours. Hs-cTnT assay
is more precise in detecting more subtle elevations indicative of cardiac
injury.34 Canadian Cardiovascular Society guidelines strongly recommend
every day TnT measurements for 2–3 days after surgery in high-risk
patients.35
Swan-Ganz Catheter and Arterial Waveform-

derived Cardiac Output
Elevated pulmonary artery wedge pressure and left ventricular end-
diastolic pressure can arise from decreased left ventricular compliance
from ischemia. The presence of tall V waves in the PA waveform suggests
mitral insufficiency. Systolic dysfunction can lead to low mixed venous
oxygen saturation and low cardiac output calculated by Swan-Ganz catheter.
Hypovolemia as a cause for hypotension can be easily ruled by measuring of
stroke-volume variation (SVV). Thereby, it can give a clue toward myocardial
dysfunction as a potential cause of decreased cardiac output.
Transesophageal Echocardiography
Regional wall-motion abnormalities are highly sensitive and specific
indicators of myocardial ischemia.36 Transesophageal echocardiography
(TEE) is now an essential and vital part of monitoring in such patients.37
Angiography
In patients with PMI as confirmed by biomarker assays or TEE, CAG
ultimately defines the cause of ischemia. CAG can very well differentiate
between type 1 ischemia (plaque instability) or type 2 ischemia (demand-
supply mismatch). Type 1 ischemia can be effectively addressed by
the PCI.
RISK PREDICTION
Perioperative risk can be stratified with the help of the revised cardiac risk
index (RCRI).38 Echocardiography gives us a lot of information in patients
undergoing high-risk surgery. Any valvular abnormalities and myocardial
dysfunction can independently predict adverse cardiac events after the
noncardiac operation.38,39 ACC and the American Heart Association (AHA)
2014 guidelines have suggested the use of online National Surgical Quality
Improvement Program (NSQIP) risk calculator.40,41
Preoperative cardiac biomarkers strongly predict PMI and mortality.42,43
Magnitude and time of elevation of troponin are related with the
mortality risk found in a study.44 Additionally, natriuretic peptide such
as N-terminal pro-BNP can also independently predict PMI.43,45
Raised BNP levels imply increased ventricular filling pressures which
need to be optimized preoperatively. Troponin and/or NT-pro-BNP
monitoring can potentially make us understand the pathophysiology of
PMI. Even different causes of PMI can be distinguished using these
biomarkers.
Other interesting biomarkers such as proinflammatory lipoprotein-

associated phospholipase A2 (Lp-PLA2) also been studied to predict the
risk of any major cardiac event.46,47 Such novel biomarkers can be useful in
such patients in the future.
PREVENTION AND MANAGEMENT

Prevention of PMI is always the aim of the perioperative physician and
anesthesiologist. Thorough history, previous health records, and a detailed
and meticulous physical examination are very helpful to estimate the risk
of CAD. Risk stratification of such population is essential so that aggressive
preventive measures can be taken.
Patients with limited functional capacity and having a risk of major
adverse cardiac event (MACE) higher than 1% are recommended to
undergo preoperative cardiac stress testing.48 Significant CAD can be
managed by a cardiac specialist with proper management strategies of
revascularization. Invasive cardiac investigation and interventions are not
generally recommended for patients with stable disease, based on the result
of landmark coronary artery revascularization prophylaxis (CARP) trial.49
These patients should be stabilized by optimizing their medical condition.
Surgical stress response should be minimized.50 Appropriate drug therapy
has been suggested to reduce ischemic complications.
Reduced postoperative hemoglobin levels carry a high rate of
complications.51-53 However, a blood transfusion may not offer advantages
always to asymptomatic patients. It is suggested to follow a restricted
transfusion strategy to symptomatic patients having hemoglobin levels less
than 8 g/dL.45
Pharmacologic Treatment and Prophylaxis

Aspirin has got a vital role in the acute management of spontaneous ACS
and also in prophylaxis strategies. Aspirin reduces platelet aggregation and
has antithrombotic effect.2 However, the Perioperative Ischemic Evaluation
(POISE)-2 trial found that it elevated the probabilities of major bleeding.54
Patients already receiving a beta-blocker and statin, should continue
these drugs during the perioperative period. It was found that aspirin and
statin therapy can offer substantial cardiac protection.55 If angiotensin-
converting enzyme (ACE) inhibitors are withheld considering the risk of
aggravating the risk of intraoperative hypotension, they can be restarted
postoperatively.56 In the perioperative period, beta-blockers can be
commenced even if the patient is not on chronic beta-blocker use. However,
to assess effectiveness, it is preferred to begin beta-blocker therapy at least
1 week before surgery.56 Alpha-2-adrenergic receptor agonists can attenuate
the stress response by dilating poststenotic coronary vessels. However, these
proposed benefits suggested in POISE-2 trial are not reflected in general

rates of cerebrovascular event, myocardial ischemia or mortality.
Perioperative clinician must be capable enough to manage unprecedented
cardiac events acutely in all patients. Recognizing and managing myocardial
injury is essential during crucial intraoperative and postoperative periods.
Conditions increasing the stress on the heart (tachycardia, anemia, etc.)
must be avoided. Monitoring as per American Society of Anesthesiologists
(ASA) should be carried out along with more invasive monitoring for high-
risk patients, e.g. central venous catheter placement with a pulmonary artery
catheter, arterial line placement, cardiac output measurement instruments,
and TEE.
CONCLUSION
Conventionally, the focus of PMI is always on CAD, yet recent evidence
suggests that noncoronary causes of PMI should not be ignored. It is
imperative to be aware of underlying pathophysiological mechanisms of
PMI so that both effective preventive measures and treatment strategies can
be applied. Better identifying high-risk patients is the first step in preventive
measures.
ACKNOWLEDGMENT
Authors wish to acknowledge the contributions of Dr Monish S Raut,
Senior Consultant, Artemis Hospital Gurgaon toward the preparation of
this manuscript.
KEY POINTS
• Revised cardiac risk index is useful in preoperative risk stratification.
Recently, National Surgical Quality Improvement Program has also been
added.
• Addition of marker like troponin to the scoring risk index will better predict
adverse cardiac events.
• Appropriate invasive monitoring should be used in such susceptible patients.
• Electrocardiography can be substantially used for early detection of
myocardial injury in the postoperative period.
• Mismatch between myocardial oxygen supply and demand should be
minimized.
• Perioperative stressful triggers such as hypoxia, electrolyte imbalance,
etc. should be reduced.
• Maintenance of coronary perfusion pressure is vital by appropriate use of
vasopressors and optimizing intravascular fluid balance.
• Myocardial oxygen delivery should be optimized by correcting anemia and
induction of coronary vasodilation.
• Judicious use of inotropic-vasopressor infusions to support hemodynamics
along with due consideration for the possible need of extracorporeal
membrane oxygenation (ECMO) and intra-aortic balloon pump.
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CHAPTER
16 Management of Hyperglycemia
in the Perioperative Period
Pallavi Ahluwalia, Payal Jain
INTRODUCTION
Literature clearly shows the relation between perioperative blood glucose
(BG) control and incidence of adverse clinical outcomes like cerebrovascular
accidents, myocardial infarction, diabetic ketoacidosis (DKA), hypoglycemic
episodes, postoperative wound infections, and length of stay.1-3 The
prevalence of diabetes is increasing. In the South-East Asia region, about
71 million people were estimated to be living with diabetes in 2010 and
an equal number had impaired glucose tolerance. If left uncontrolled, the
burden will almost double by 2030 in this region. Perioperative hyperglycemia
has been seen in almost 15–45% of patients undergoing general surgery.
Diabetes accounts for up to 10% of healthcare expenditure in developed
nations, and these huge costs are related in part to the excess number of
hospital admissions.4
Hyperglycemia or dysglycemia is the most common issue encountered
by anesthesiologist in perioperative settings. Anesthesiologists play a
crucial role in the assessment, initiation of treatment, and management
of these patients during the perioperative period. Due to varied spectrum
of population, it is extremely difficult to follow one standard protocol for
perioperative BG control, which is appropriate for all patients. Risks can
be reduced by early identification and timely intervention. The overall goal
of management is avoidance of hypoglycemia and providing adequate BG
control, which lies midway between strict control (BG levels of 78–108 mg/dL)
and overt hyperglycemia (BG levels of >200 mg/dL) and. The reports suggest
evidence of perioperative hyperglycemia is between 20% and 40% following
noncardiac general surgery2,5,6 and nearly 80% in patients following cardiac
surgery.7,8
DIAGNOSTIC CRITERIA FOR DIABETES MELLITUS

The American Diabetes Association (ADA) has set the following criteria for
the diagnosis of diabetes mellitus:
• A fasting plasma glucose level (defined as plasma sample taken after no
calorie intake for 8 hours) greater than or equal to 126 mg/dL.
Management of Hyperglycemia in the Perioperative Period 227
• Following “oral glucose tolerance test”, a 2-hour plasma glucose level

greater than or equal to 200 mg/dL. Test is done after a glucose load of
75 g (glucose in anhydrous state dissolved in water).
• HbA1c ≥ 6.5%. This test is recommended in a standard laboratory
utilizing a method that is the National Glycohemoglobin Standardization
Program (NGSP) certified. Test is standardized by the Diabetes Control
and Complications Trial (DCCT) assay.9
• Patients presenting with classic symptoms because of hyperglycemia or
in hyperglycemic crisis, with a random plasma glucose level more than
200 mg/dL are considered diabetic.
IMPLICATIONS OF SURGERY ON BLOOD SUGAR LEVELS

Majority of patients with hyperglycemia are usually diagnosed cases of
diabetes but 12–25% of patients are without any prior history of diabetes
before surgery,2 and are often in a state described as “stress hyperglycemia”.10
Perioperative problems in a diabetic patient can be categorized according to
the site of surgery, magnitude of tissue damage, given, intraoperative fluid
shifts, type of anesthesia, and preoperative control of blood sugar levels.
Stress response to surgery leads to secretion of cortisol, catecholamine,
and growth hormone which inhibit glucose homeostasis by stimulating
gluconeogenesis and glycogenolysis leading to increase in sugar levels
and ketosis. Secondly, damage of tissue due to surgical procedure starts a
reaction in the body causing release of inflammatory cytokines such as tumor
necrosis factor (TNF), interleukin 1, interleukin 6, which causes decrease
insulin sensitivity leading to hyperglycemia. Additionally, an increase
in stress hormones leads to an increase in free fatty acid concentrations
which limits insulin-stimulated glucose uptake. All these reasons lead to
altered body responses to glucose loading which can continue up to 3 weeks
postoperatively.
TYPES OF ANESTHESIA AND ITS EFFECT ON

BLOOD GLUCOSE
General anesthesia leads to higher incidence of hyperglycemic episodes
because of relatively more release of stress hormones like catecholamines,
cortisol, and glucagon in comparison to local or epidural anesthesia.11
Combined spinal-epidural anesthesia is a preferred mode of anesthesia
as it attenuates the neurohormonal stress response of body by decreasing
catecholamine release and thereby preventing elevation in BG levels.12
Also, it blunts the stress response mediated by sympathetic efferent signal
blockade, reducing enhanced fibrinolytic activity which is normally the root
cause of hyperglycemia.13 However, one must be aware that the diabetic
patients are quite prone to autonomic neuropathies. Injudicious use of local

anesthetics can lead to life-threatening consequences such as hypotension
due to blunted compensatory baroreceptor reflex mechanism. Regardless
of technique used, it should lead to rapid recovery to avoid concealment
of hyper as well as hypoglycemic episodes.11
Diabetes is a multisystem disease affecting the peripheral nerves as well,
but studies have shown that plexus block like brachial plexus block has
shown the same efficacy as in normal patients for shoulder surgeries but
for distal surgeries like that of elbow, supplementation may be necessary.14
ANESTHETIC DRUGS AND THEIR EFFECTS ON

BLOOD GLUCOSE
• Benzodiazepines and opioids produce hormonal and metabolic stability
by decreasing adrenocorticotropic hormone (ACTH) secretion and
reducing the production of cortisol in high doses. They act by reducing
the sympathetic stimulation thereby decrease the glycemic effect of
surgery.15 When given in usual sedative doses, these effects are minimal.
• Atropine can mask the symptoms of hypoglycemia due to its
anticholinergic action.
• Inhalational agents lead to increase in blood sugar levels. This effect
is mediated in a dose-dependent manner by inhibiting the insulin
response to glucose.16-18
• Etomidate decreases cortisol production by blocking adrenal
steroidogenesis (11β-hydroxylase enzyme is blocked) thus decreases
blood sugar levels.19,20
• Propofol has no effect on insulin secretion. However, due to lipid
formulation, its metabolism and excretion are decreased in diabetic
patients thus leading to delayed awakening. Moreover, it may lead
to excessive hypotension especially in patients with autonomic
neuropathies.18,21
• Ketamine stimulates sympathetic nervous system and thus leads to
hyperglycemia.22
• Thiopentone causes either no change in the BG levels or slight
hyperglycemia due to decrease glucose tolerance.23
• Muscle relaxants do not have direct effect on glucose metabolism, but
in patients with neuropathies or neuromuscular junction abnormalities
aberrant response may occur.24
• Reversal agent sugammadex is a cyclodextrin molecule that is consisted
of bounded sugar. Thus, because of its chemical structure, it can lead to
increase in blood sugar levels.25
• Opioid anesthetic techniques utilizing high doses of opioids produce
hemodynamic, metabolic, and hormonal stability. However, midazolam
and fentanyl may cause hyperglycemia by reducing glucose clearance.26

In vitro studies done on rats showed reduced clearance of glucose by
fentanyl.27
• β-blockers use is associated with slower recovery from hypoglycemia.
In insulin-dependent diabetics, beta-blockers can prolong, enhance, or
alter the symptoms of hypoglycemia, while hyperglycemia appears to
be the major risk in noninsulin-dependent diabetics. Beta-blockers can
potentially increase BG concentrations and antagonize the action of oral
hypoglycemic drugs.28
ASSESSMENT DURING PERIOPERATIVE PERIOD AND

MANAGEMENT GOALS
In a patient with diabetes, the perioperative period can be quite challenging for
the anesthesiologists as it is important to manage uncontrolled hyperglycemia
against avoiding hypoglycemia. The aim of the anesthesiologists will be to:
• Decrease morbidity and mortality by avoiding DKA as well as hypo
glycemia.11,29
• Assess airway of the patients as these patients are prone to diabetic
cheiroarthropathy;30 a condition leading to limited joint mobility because
of glycosylation of collagen present in joints especially axial and atlanto-
occipital joints, which could lead to difficulty in intubation because of
restricted neck extension. It is checked with the help of palm print sign
and prayer sign.
• Assess for autonomic neuropathy as this affects the compensatory
mechanism of the cardiovascular system (e.g. baroreceptor reflex) for
any change in intravascular volume or patient position. Moreover, these
patients are prone to silent myocardial ischemia.
• Be cautious for gastroparesis which may precipitate regurgitation and
aspiration.
• Assess the respiratory system. Pulmonary microangiopathies and chronic
systemic inflammation of diabetes lead to decrease in lung volumes,
diffusing capacity, and hypoxia-induced ventilator drive.
• Maintain intravascular volume and electrolyte check.
• Look for diabetic nephropathy.
• Regulate the hypoglycemic drug and insulin intake prior to surgery, and
finally.
• Establishment of certain glycemic target levels,11,29 <180 mg/dL in sick
patients and <140 mg/dL in otherwise stable patients.4
GLYCEMIC GOALS IN PERIOPERATIVE PERIOD

Based on clinical evidence and in view of lack of well-conducted clinical
trials, consensus favors moderate glycemic goals in the perioperative period.
American Diabetes Association and Joint British Diabetes Societies have

recommended BG level between 140 mg/dL and 180 mg/dL keeping
the acceptable range between 72 mg/dL and 216 mg/dL. The study
“Normoglycemia in Intensive Care Evaluation-Survival Using Glucose
Algorithm Regulation” (NICE-SUGAR) suggested that a BG target of
140–180 mg/dL (<10 mmol/L) during entire perioperative period leads
to decreased morbidity and mortality than a narrower and restrictive
approach, targeting BG between 81 mg/dL and 108 mg/dL (4.5–6 mmol/L)
as recommended earlier. Even Society for Ambulatory Anesthesia (SAMBA)
guidelines recommend the target BG levels of <180 mg/dL during the
perioperative period. Thus, in nonurgent cases, fasting blood sugar levels
of 70–180 mg/dL are acceptable, above which correction is needed.30 No
standard rule has been given for postponing the case, but elective surgeries
should be deferred in patients with a unstable and compromised metabolic
conditions like DKA, HHS, etc.31-33
NUTRITION AND NUTRITIONAL INTAKE

Diabetic patients are generally recommended to be taken as first case in
list to avoid prolonged fasting. Nutritional supplement in diabetic patients
with dextrose solution is generally needed only after prolonged fasting of
36 hours or more as incidence of hypoglycemia before this time frame is
less. A meta-analysis showed that less of carbohydrate but higher intake
of monounsaturated fatty acid formulas are preferable in type 1 as well
as type 2 diabetic patients as they improve glycemic control.34 This can
have implications in elective cases as well as intensive care unit (ICU)
care. The basal metabolic requirements for in-hospital patients can be met
by providing 20–30 calories/kg/day, while in critically ill patient’s caloric
requirement decreases to approximately 15–25 calories/kg/day.35 A diet
providing intake of 1,800–2,000 calories/day is appropriate for most patients.
Diabetic patients are generally considered as full stomach patients as they
have reduced gastric emptying time due to autonomic neuropathy leading
to gastroparesis.35
APPROACHES TO IMPROVE PERIOPERATIVE

GLYCEMIC CONTROL
Patient’s on Oral Hypoglycemic Agents
Posted for Surgery
The preoperative diabetic control of patient is a customized approach
according to various factors like the type of diabetes, the period of fasting
pre- as well as postoperatively, type and extensiveness of surgical procedure,
prior medication being taken and level of metabolic control prior to surgery.
Frequency, dose, type of oral hypoglycemic agent (OHA) and dose of

insulin would be tailored to the extent of avoiding overt hyperglycemia as
well as hypoglycemia. However, currently, there are no prospective trials
examining surgical outcomes after randomly allocating diabetic patients to
either no diabetic treatment or treatment (as it would be deemed unethical
to randomly allocate patients with diabetes to no treatment) or to show
the role of oral medication before surgery, the consensus, in general, is
to continue OHAs up to a day prior to surgery. The recommendations for
different OHA is given in Table 1.
Sulfonylureas group of drugs (glibenclamide, glimepiride, and glipizide)
leads to insulin production which may cause hypoglycemia during the
preoperative period in a nil per oral (NPO) patient and thus should
be avoided on the day of surgery.36,37 As sulfonylureas are known to be
notorious for blocking the myocardial potassium adenosine triphosphate
(ATP) channels responsible for anesthetic-induced preconditioning, it is
recommended that they should be avoided during the entire perioperative
period. However, if taken mistakenly on the day of surgery, surgery can
be done under careful glucose monitoring and intravenous (IV) dextrose
should be kept stand by.38,39 Biguanides (metformin) mechanism of action is
through making tissues sensitive to insulin and preventing gluconeogenesis.
Its perioperative use is debatable as it may lead to renal impairment
intraoperatively causing hemodynamic instability, decreased renal blood
Table 1: Recommendations for oral hypoglycemic agent (OHA) for minor and
major surgeries.
Day of surgery (if Day of surgery (if
minimally invasive extensive surgery,
and patient can hemodynamic
Day before resume intake the changes, fluid
Oral hypoglycemic agent surgery same day) shifts anticipated)
Sulfonylureas (glibenclamide, Take Withhold Withhold
glimepiride, glipizide)
Thiazolidinediones Take Take Withhold
(pioglitazones, rosiglitazones)
Biguanides (metformin) Take Take Withhold
Glucagon-like peptide 1 Take Withhold Withhold
agonists (sitagliptin,
linagliptin)
DPP-4 inhibitors (exenatide, Take Take Take
liraglutide)
Alpha glucosidase (acarbose, Take Withhold Withhold
miglitol)
flow, and increased chances of lactic acidosis.38,40 Therefore, in cases where

major fluid shifts are anticipated this is withheld on the day of surgery.
Alpha-glucosidase inhibitors group of drugs (acarbose, miglitol) decrease
the absorption of glucose after meals. This is mediated by decreasing the
absorption of oligosaccharidases and disaccharidases from the intestinal
luminal, brush border. Therefore, this drug has no effect during the
preoperative fasting states, and thus should not be given until enteral
feeding starts.41 Thiazolidinediones (pioglitazone, rosiglitazone) lead to fluid
retention and thus these drugs are discontinued29,38,39,42 if major fluid shifts
are anticipated. Glucagon-like peptide 1 (GLP-1) agonists group (exenatide,
liraglutide) are stopped on the day of scheduled surgery because they
are known to cause gastroparesis, leading to the delayed resumption of
gastrointestinal function during the recovery phase. Dipeptidyl peptidase-4
(DPP-4) inhibitors group of drugs (sitagliptin, linagliptin) might be
continued as they work in a glucose-dependent mechanism thus there are
lesser chances of hypoglycemia.29
Patients on Insulin Posted for Major Surgery

A constant source of insulin is always required in our body as insulin works
by not only inhibiting gluconeogenesis but it also helps in preventing the
breakdown of fats into fatty acids and further transformation of fatty acids to
ketones thus avoiding ketoacidosis. Thus, a basal insulin levels must always
be maintained even in fasting state.11 This emphasizes that due to fear of
hypoglycemia, abrupt withdrawal of insulin is not recommended.
Glucose monitoring should be done 4–6 hourly in patients with NPO
status and if required, supplemental glucose infusion may be given in the
prescribed range.
Enhanced recovery after surgery (ERAS) pathways suggest carbohydrate
load (as compared to traditional overnight fast) to improve insulin resistance.
However, many patients receive 4–8 mg dexamethasone intravenously
as antiemetic to decrease side effects like nausea and vomiting and this
may reduce the benefits of carbohydrate loading and may instead cause
hyperglycemia. Moreover, ERAS programs are not suitable for patients with
high BG levels or impaired glucose tolerance.
In order to avoid insulin stacking, the patient should not be given human
insulin more frequently than 6 hourly for correction of hyperglycemia. For
patients on insulin, the preoperative regimen should be changed as given
in Table 2.
Patient on continuous subcutaneous insulin infusion (CSII) pump can
continue with his daily infusion and rest types of insulin should be modified
as given above. Variable rate insulin infusion (VRII) has the disadvantage
that its use in daycare surgery is still under study and abrupt withdrawal
can lead to DKA.43
Table 2: Recommendations for change in insulin regimen.

Insulin regimen Day before surgery Day of surgery
Continuous No change required, minimal No change required, mini
subcutaneous insulin disruption to normal diabetes mal disruption to normal
infusion (CSII) management diabetes management
Variable-rate Theoretically best control of Titrated according to BG
intravenous insulin blood sugar titrated according
infusion (VRIII) to blood glucose (BG)
Long-acting, peakless No change required 75–100% of morning dose
insulin
Intermediate-acting No change in daytime dose, 50–70% of morning dose
insulin 75% of dose taken in the
evening
Fixed combination No change required 50–75% of morning dose
(70/30 or 75/25 of intermediate-acting
premixed) insulin (NPH)
Short- and rapid- No change required Hold the dose
acting
Instructions regarding preoperative insulin as per SAMBA guidelines are

modest reductions in the dose of long-acting insulin and avoidance of short-
acting insulin on the day of surgery.44 Elective cases, in cases where BG
levels are well controlled and no major hemodynamic shifts are anticipated
with duration of surgery lasting for less than 4 hours, the abovementioned
rules for oral hypoglycemic drugs and insulin can be followed.
If the patient is critically ill, BG poorly controlled at home or major
hemodynamic changes are anticipated or long duration of surgery then shift
the patient to continuous insulin infusion.
Administering subcutaneous insulin in multiple doses should be avoided
to hastily stacking them and causing a subsequent hypoglycemia.
In case of emergency procedures or intraoperatively, when rapid
correction of hyperglycemia is important along with avoidance of hypo
glycemia, the simple and effective mean of dose calculation is given by the
1800 Rule for patients already on insulin.32,45
The “1800” Rule

The 1800 Rule is an estimation of glucose neutralization in response to
1 unit insulin. For instance, if a patient receives a total dose of insulin of
40 units daily, the correction factor is calculated as follows:
Correction factor = 1,800 divided by the total daily dose (TDD) of insulin
1,800 ÷ 40 = 45 mg/dL.
Since these are assumptions and taking into consideration, the various
studies and trials conducted, it can be assumed that 1 unit of insulin would
decrease glucose by 35–45 mg/dL.
For those with no history of insulin intake, it is assumed that the total
correction insulin dose to be given can be calculated such as 1–4 units of
rapid-acting insulin per every 50 mg/dL (2.8 mmol/L) for intended glucose
level reduction. Another alternative is intravenous regular insulin use, but
its disadvantage is that it peaks onset occurs in minutes and the duration of
action is 30–40 minutes. Therefore, it may result in rapid and wider swings
in BG levels.
NEW AND IMPROVED INSULIN DELIVERY DEVICES

Various advances in newer technology over last few decades have helped in
improving management and achieving glycemic goals. For insulin delivery,
a newer technique includes intranasal insulin and continuous subcutaneous
insulin infusion. For continuous glucose monitoring, a glucose oxidase-
coated sensor is inserted subcutaneously, which measures the interstitial
glucose concentration levels and the values are then converted to a plasma
glucose estimate. It seems to be a promising modality. Finally, pancreatic
and islet cell transplantation and immunotherapy are still in trial.
GLYCEMIC MANAGEMENT IN INTRAOPERATIVE PERIOD

Various trials have pressurized on the fact that surgical stress and anesthesia
evokes hyperglycemic response in a diabetic patient. Society for Ambulatory
Anesthesia; American Association of Clinical Endocrinologists and American
Diabetes Association (AACE/ADA) joint guidelines; American College of
Physicians (ACP); ADA recommend BG levels between 150 mg/dL and
200 mg/dL throughout the surgery.46 Perioperative BG levels targeted during
surgery are chiefly determined by various factors like the surgical time, the
extent of surgical procedure, the type of anesthetic technique used, time to
resume oral intake, and routine antidiabetic therapy prescribed.
Every patient should get BG checked after every 2 hours, with a target
of 180 mg/dL. For the intraoperative period, the arterial blood gas (ABG)
analysis, the point-of-care BG measurement or glucometer devices can be
used to measure capillary BG measures, which can be used for titration of
insulin.
Subcutaneous insulin is appropriate for short/minor procedures or
ambulatory surgery, surgeries that are minimally invasive or with hemo
dynamic stability, operation time less than 4 hours.41 Intraoperatively, dose
of SC insulin can be calculated either by 1800 Rule or if patients TDD is not
available or patient takes oral hypoglycemic at home a sensitivity factor of
40 can be taken for safe calculations.
Correctional dosing with rapid-acting insulin can be calculated with the

following formula:
Measured glucose – 100/insulin sensitivity factor.
Insulin sensitivity factor is equal to 1,800 divided by the patient’s TDD
of insulin. The TDD is equivalent to the patient’s daily amount of basal,
prandial, and correctional insulin. Should TDD not be available or if a patient
is using only oral medications at home, a sensitivity factor (denominator) of
40 provides a safe calculation for a correctional insulin dose.
For complex surgical procedures, the most efficient method is variable
rate IV insulin infusion for achieving BG control.41
Table 3 enlists a simplified version of IV insulin to be given intraoperatively.
For adjusting the insulin infusion according to BG levels, an increase or
decrease of 25 mg/dL of BG levels from baseline is taken after every 2 hours.
Few simple interventions can help to improve BG control. For example,
the use of normal saline instead of dextrose as a solution for giving
antibiotics or other medications. Glucose-insulin-potassium (GIK) infusion
technique was being used traditionally but the main disadvantage of this
continuous drip is that it does not permit any individual manipulation of
glucose or insulin levels so it is recommended for BG maintenance, once a
specific glycemic level is achieved.47 This method of BG control is now more
of a historic value.
Determination of BG is preferentially made using venous plasma
or serum samples. Arterial and capillary blood yields glucose values
approximately 7% higher than those for venous blood, and whole-blood
Table 3: Insulin infusion and its required change of rate as per blood glucose (BG)
levels.
Blood glucose Blood glucose decreased
Blood glucose increased >25 mg/dL by >25 mg/dL (after 2
levels (mg/dL) (after 2 hours) hours) Remarks
>250 ↑ 3 U/h No change •• BG checked
every 2 hours if
increased
•• If BG levels
decreased then
to be checked
after every 15–30
minutes
200–250 ↑ 2 U/h No change
150–200 ↑ 1 U/h No change
100–150 No change Hold
70–100 Hold
determinations are usually 15% lower than plasma or serum values. Urine
glucose monitoring is not reliable. Thus, in practice, a venous sample is
preferred for BG levels.48
HYPOGLYCEMIA
Hypoglycemia is defined as BG level less than 70 mg/dL.49 It is one of the
most common complications that occurs with tight glycemic control. Under
general anesthesia, detection of hypoglycemic symptoms can be a bit tricky
because of masking of altered mental status due to hypoglycemia. Thus, the
anesthesiologist should be vigilant for the same. Frequent BG monitoring,
communication with the perioperative provider about the dose and type
of drug or insulin given, conservative BG targets and treatment guidelines
based on insulin sensitivity may help in reducing intra- and postoperative
hypoglycemia.50
GLYCEMIC MANAGEMENT IN
POSTOPERATIVE PERIOD
Because of various factors like postoperative complications and anesthetic
side effects BG control during the postoperative stage may be tricky. BG
levels should be assessed every 2 hours and a correction dose of insulin
should be given for levels greater than 180 mg/dL. Insulin should be dosed
while keeping in mind, the risk of hypoglycemia. Usually, subcutaneous
insulin is preferred in immediate postoperative period for correction of BG
levels but if the patient’s condition deteriorates then intravenous insulin is
started.
For patients who have to be kept nil per oral, generally only basal insulin
plus correctional dose of insulin for BG levels greater than 180 mg/dL is
preferred, while in patients with good nutritional intake, prandial insulin is
also added with basal and correctional insulin regimen.36 A study suggested
that this basal-bolus regimen reduced the postoperative complications
like surgical site infection significantly and lead to lesser incidences of
hypoglycemia than the use of protamine or premixed insulin.
The dose of insulin to be given subcutaneously can be calculated on the
basis of the following methods:
• Patients who are not accepting orally are started with a basal dose of
0.1–0.25 U/kg/day with lower values for patient sensitive to insulin. For
patients resistant to insulin, the dose can go high up to 0.3 U/kg/day
also.
• For patients accepting normal meals, basal insulin 0.1–0.25 U/kg/day
can be given along with 0.1–0.25 U/kg/day of rapid-acting insulin. In
both scenarios, correctional insulin is to be given if BG goes higher than
180 mg/dL.
In hospitalized patients, generally, oral medication is not recommended

because of erratic results. However, recently DPP-4 inhibitors have been
studied and suggested during the perioperative period for managing BG
levels in hospitalized patients.
Patients who were on intravenous insulin and are now being shifted to
subcutaneous insulin require special care. Calculation of dose can be done
by determining the TDD of insulin intravenously. Of the dose calculated,
70% to be given as basal insulin and 30% of the calculated dose as prandial
insulin for patients tolerating a normal diet and for those not taking orally
the dose should be reduced by 25% to be given only as basal insulin.
In order to avoid hyperglycemic crisis subcutaneous basal insulin is
administered 2 hours before stopping the intravenous insulin. Patients
without any prior evidence of diabetes and HbA1c lesser than 6.5 can
be transferred without any basal insulin. In all scenarios, continuous
monitoring is recommended and correctional insulin is given; keeping a
watch for hypoglycemia. The recommendations for target BG concentration
are listed in Table 4.51-53
If for some reason BG levels remain low postsurgery, then a dextrose
infusion at a rate of 5–10 g of glucose per hour is required to avoid
hypoglycemia and risk of ketoacidosis. Additionally, if a patient cannot
accept oral intake for a long period of time, total parenteral nutrition
(TPN) should be started. But nutrition by enteral feeds should be resumed
as soon as possible as it has fewer infectious complications, promotes
earlier restoration of gut function, is cost-effective and has shorter duration
of hospital stay as compared to TPN. For mimicking physiologic insulin
replacement, a basal long-acting basal insulin dose along with a short- or
rapid-acting insulin dose following meals can be started and rapid-acting
supplemental insulin can be given to manage hyperglycemia if required.
Basal insulin levels should be maintained after stopping intraoperative
IV insulin. This is of special importance in type 1 diabetes patients, as
Table 4: Recommended guidelines regarding target blood glucose concentrations.

National organization Recommendations for critically ill patients
Society of Thoracic Surgeons
51
•• Target blood glucose level <180 mg/dL
•• If patient is in ICU for >3 days, then
upper limit of 150 mg/dL
American Association of Clinical Target blood glucose level between 140 mg/dL
Endocrinologists (AACE) and and 180 mg/dL
American Diabetes Association
(ADA) Consensus Statement on
Inpatient Glycemic Control52
American College of Physicians53 Target blood glucose level of 140–200 mg/dL
the baseline insulin requirements must be met to avoid DKA. The basal
insulin dose is calculated using the “Miami 4/12”29 rule or is estimated to
50–80% of the intraoperative IV total insulin required (assuming that the BG
control was achieved within the desired range). Those patients who receive
IV insulin intraoperatively, it is desirable to continue IV insulin alongside
a dextrose infusion until the patient can resume enteral feeds without
difficulty. Once the patient starts taking orally, the intravenous drips can
be titrated and glycemic control measures followed preoperatively may be
restarted.
Blood glucose measurements during the intraoperative as well as
postoperative period can be done by either central-laboratory device
(CLD) or point-of-care (POC) devices.54 Various studies suggest avoidance
of the POC device for BG measurements in the perioperative period. They
advocate the use of CLD for BG measurements.
SPECIAL SCENARIOS
Daycare Surgery
For daycare minor surgeries, that are unlikely to cause major fluid shifts
and hemodynamic variations patients with type 1 or type 2 diabetes can
be managed by either IV or subcutaneous insulin. For the management of
type 2 diabetic patients on OHAs, the above-prescribed guidelines should
be followed. For emergency surgeries, BG should be monitored more
frequently. Time of the last intake of a sulfonylurea dose must be noted, as
progressive absorption of the drug may disturb glycemic control.
Cardiac Surgery
Cardiac surgeries increase the insulin requirements. Overall, perioperative
control of hyperglycemia via continuous insulin infusion was associated with
decreased incidence of deep sternal wound infection, shortened hospital
length of stay, reduced rates of recurrent ischemia, improved long-term
survival, and significantly decreased morbidity in a large number of cardiac
surgical patients. As such, it is now a globally accepted standard practice
of care, although the precise stringency of control, i.e. tight versus moderate,
timing and duration of intravenous therapy remain matters of debate.55
Obstetric Patients
Pregnancy is a state of relative insulin resistance. Moreover, drugs like
ritodrine used for labor and dexamethasone used for induction of fetal
lung maturation worsens insulin resistance. Before the induction of labor,
patients can continue to follow their routine diabetic medications; but
if labor is extended, the risk of hypoglycemia to mother as well as fetus

increases. After delivery of placenta, insulin requirement drops drastically
and at this point, dose reduction of insulin (or stopping insulin altogether)
in gestational diabetes and frequent monitoring is required. During surgery,
hyperglycemia should be managed and BG monitoring every 30 minutes
is done to decrease the risk of hypoglycemia in the newborn or reduced
incidence of postoperative wound infections in the mother.
Diabetic Ketoacidosis
The Joint British Diabetes Societies Inpatient Care Group has defined DKA
as triad of hyperglycemia, ketonemia, and metabolic acidosis.56
Diagnosis of DKA is done as follows:
• Ketonemia >3 mmol/L or ketonuria >2+ by dipstick method
• Blood sugar >200 mg/dL
• Venous pH <7.3 or serum bicarbonate <15 mmol/L.
During treatment for DKA, the emphasis is on correction of dehydration
and clearance of ketones while controlling the blood sugar levels. Symptoms
include respiratory distress, malaise, vomiting, abdominal cramps, fruity
odor, drowsiness, coma. Signs include tachycardia, acidotic breathing,
depressed consciousness, and abdominal tenderness.
Fluid correction is done by administering 15–20 mL/kg of fluid in
the first hour, this rate is halved over next 4 hours. Normal saline and
ringer lactate both have been studied for initial resuscitation. Colloids are
not recommended. Further fluid therapy is guided using urine output,
electrolyte balance or central venous pressure (if inserted). Total deficit has
to be corrected slowly over 24 hours to avoid fluid overload. If need be,
advanced hemodynamic monitoring and vasopressors are used.
Regular insulin infusion is started at a fixed rate of 0.1 units/kg/hour
with the aim to decrease the blood sugar levels by 50 mg%/hour. The rate
can be increased if the drop is not adequate, but once sugar levels come
down to 250 mg% dextrose is added to the fluid to continue fixed insulin
rate. Potassium is supplemented only if levels are <3.3 mEq/mL. Use of
bicarbonates is controversial but 50–100 mmol can be given if pH is <7.0.
Phosphate supplementation is done if levels are <1 mg/dL or in presence
of cardiac dysfunction, anemia, or respiratory muscle weakness. Regular
2 hourly monitoring of BG, serum electrolytes, blood urea nitrogen,
creatinine, osmolality, and acid-base status should be done. As DKA
resolves; the patient is started on his previous subcutaneous regimen with
an overlapping phase of subcutaneous dose and intravenous insulin.
CONCLUSION
Glycemic control in the perioperative period is challenging. Various
protocols defining perioperative blood sugar control are described in
the literature. One must remember that BG control during perioperative
period requires careful monitoring of BG, electrolytes, and acid-base status.
Good perioperative glucose management can help avoid various surgical
complications and hyper- or hypoglycemic squeal, hence reduce morbidity
and mortality.
CONFLICT OF INTEREST
Nil.
KEY POINTS
• Hyperglycemia (blood glucose > 180 mg/dL) has adverse clinical outcomes
during the perioperative period. Maintaining adequate BG levels in the
desired range can reduce morbidity and mortality.
• For BG measurement, the recommended gold standard is a venous
plasma sample, which is tested in clinical laboratory.
• Aggressive insulin therapy to achieve a tight glucose control in a target
BG range between 80 mg/dL and 110 mg/dL, significantly increases
chances of hypoglycemia and therefore is not proven to be beneficial in
perioperative settings in surgical patients.
• Perioperatively target BG range between 140 mg/dL and 180 mg/dL should
be maintained to avoid overt hyperglycemia as well as hypoglycemic
crisis.
• Because of the heterogeneity of the patient population and the surgical
procedures, a single management protocol cannot ensure optimal blood
sugar control for all.
• Hospitals and institutions must have their own policies or guidelines for
dysglycemia management to cover a variety of treated patients ranging
from ambulatory to critically ill.
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CHAPTER
17 Challenges and Issues in

Daycare Arthroplasty
Surinder Mohan Sharma, Himanshu Suri
INTRODUCTION
Advancement in medical care has ensured longevity, resulting in an
increase in the aging population with attendant medical problems including
osteoarthritis. This has resulted in an increased need for total hip and knee
arthroplasty (THA/TKA).1 A growing elderly population puts an increased
load2 on the healthcare services, including optimum utilization of hospital
beds, prolonged length of stay leading to an attendant rise in the cost of
healthcare.3
It has been seen that longer stay in the hospital is linked to a higher
morbidity and mortality.4 The last decade has seen intensive endeavors
in form of protocols labeled as enhanced recovery after surgery (ERAS)
to reduce the length of stay after joint arthroplasty. A protocol-based
multimodal anesthesia and pain management program coupled with
modified surgical techniques help patients mobilize faster. Meticulous
preoperative planning along with fast and precise conduct of surgery leads
to reduced morbidity and mortality. This, in turn, enables them to reach the
essentially unchanged discharge criteria much earlier and in many cases
after the first postoperative night or even on the day of surgery.
DEFINITION OF DAYCARE OR OUTPATIENT

ARTHROPLASTY
Daycare or outpatient total joint arthroplasty (OTJA) of the knee or the
hip joint has been differently defined as a reported stay of <23 hours5 or
hospital discharge from hospital on the day of surgery.6 Although some
patients reach the discharge criteria on the day of surgery, OTJA remains
a psychological barrier in many institutions. In addition, reimbursement
issues and concerns over safety prevent surgeons from allowing patients to
go home on the day of surgery.7
In a study, using the National Surgical Quality Improvement Program
(NSQIP), only 63 (12%) of the 529 THA patients registered as outpatients,
were discharged on the day of surgery. Similarly, only 95 (11%) of 890
patients undergoing TKA, registered as outpatients, could be discharged on
Challenges and Issues in Daycare Arthroplasty 245
the same day. In the United States, prevailing regulations allow patients to
be observed in the hospital for an extra night under the outpatient category.8
Acceptance of daycare total joint arthroplasty (TJA) by patients is deterred
by apprehension of pain and postoperative complications, delayed recovery,
and dependence on others. Most patients would prefer early discharge from
hospital if their apprehensions are allayed.9 Higher patient satisfaction scores
have been recorded in case of same-day discharge.10 Evidence regarding
the feasibility of outpatient TJA in unselected populations is seen in few
studies.11,12 For promoting wider acceptance of the technique, it is important
to address the abovementioned factors.
WHY DAYCARE TOTAL JOINT ARTHROPLASTY

Substantial high costs are associated with inpatient TJA. In today’s
economically challenged healthcare environment, these costs can be
significantly lowered (around 30%) by the adoption of daycare TJA.13 Further,
daycare TJA, unicompartmental knee arthroplasty (UKA) and THA have
shown similar safety and effectiveness compared with inpatient TJA.11,13-19 A
shorter period of hospital admission is labeled as safe and considered cost-
effective if there is no rise in 30-day readmission rate. Prolonged hospital
stay is associated with the risk of nosocomial infections. It also leads to
decreased bed availability, the prolonged waiting time for those waitlisted
for surgery. The other adverse effects reported are impairment of cognitive
function leading to dependence on others for activities of daily living.20 It
is also associated with significant locomotor impairment.21
Enhanced recovery or fast-tracking is a concept first introduced by
Henrik Kehlet, a surgical gastroenterologist. It aims at optimization of
clinical features, improving logistics, and allowing patients to recover faster,
thereby resulting in a reduced length of hospital stay (LOS). The essential
guiding principle of fast-tracking has been—“first do it better, then do it
faster.” Application of ERAS principles in TJA has reduced the average length
of stay from 9 days to 4 days without any rise in adverse effects.10,22-24
COMPONENTS OF AN OUTPATIENT TOTAL JOINT

ARTHROPLASTY PROGRAM
Important components of an OTJA program include:
• Preoperative screening focused on patient comorbidities (especially
anemia) and home environment.
• Patient education and expectation alignment.
• Minimization of intraoperative blood loss.
• Multidisciplinary pain management and early mobilization.
• Same-day postdischarge monitoring to assess the status of wound, pain,
and power of the muscles.
The shift toward daycare arthroplasty is an evolving process and in all

high volume centers, it is usually a step-up from running a well-established
fast-track TJA program. Meticulous attention to detail is required in addition
to anticipation of potential complications and having systems in place to
tackle any adverse outcomes. It entails having a well-equipped surgical
center with well-trained and goal-focused nursing staff, protocol-led
anesthetic technique, postoperative pain management program, blood
transfusion management, rehabilitation, and physiotherapy program. All
these work in unison to ensure patient safety, promote patient satisfaction
and facilitate same-day discharge.25
There is a steady rise in the daycare arthroplasty, despite various
challenges on the medical and logistic fronts. Daycare arthroplasty, in the
United States, has reportedly increased by 47% during the period 2012–2015
and is projected to grow by 77% over the next decade in comparison to 3%
projected increase in inpatient surgeries.26
PATIENT SELECTION
Establishing a stringent patient selection criterion is the most important step
in designing an OTJA program to ensure minimum adverse events (AEs)
and readmissions.27 Total joint arthroplasty on a daycare basis is generally
attempted in younger patients, preferably <65 years, as advanced age (>75
years) increases the chances of complications. Elderly patients have higher
incidence of stiffness and pain, retention of urine and a greater likelihood of
postoperative falls and thus a higher incidence of readmission within 1 year
of surgery.17,27 Patients with comorbidities, which might lead to untoward
events, are usually not considered for an outpatient procedure. A prolonged
LOS in the hospital is usually as a result of postoperative complications
arising out of poorly controlled cardiovascular disease, diabetes, or a
consequence of prolonged corticosteroid usage.5,10,28
Similarly, patients with reduced cognition, functional neurological
deficits, chronic kidney disease, obesity (BMI > 30 kg/m2), and bleeding
disorders are more likely to encounter multiple issues in the postoperative
period. Postoperative analgesia may be particularly challenging in patients
with chronic opioid use as they are usually tolerant to pain medications and
it might be better to treat them as inpatients.
Preoperative use of mobility aids is indicative of reduced functional
status of the patient and as such these patients are more likely to encounter
difficulties in mobilization after discharge. Elderly patients usually have
voiding difficulties which might pose practical challenges in the postoperative
period and hence these patients may not be suitable candidates for an
outpatient procedure. In a review of 381 consecutive TKAs, risk factors
correlating with a prolonged stay and increased hospital costs were a higher
American Society of Anesthesiologists (ASA) score (III//IV), female gender,

advanced age, history of atrial fibrillation, and patients having undergone
prior knee replacement.29
Simultaneous bilateral TKA, surgery performed for fracture, and
orthopedic complexity (e.g. bone loss or retained hardware) should all be
excluded from outpatient surgery.28 Simultaneous bilateral TKA carries an
increased risk of serious cardiac complications, pulmonary emboli, and
mortality when compared with staged bilateral or unilateral surgery.30 The
risks of these complications are too high to perform these surgeries on an
outpatient basis. Patients with prior complications of surgery or anesthesia
should also not be preferably scheduled as outpatient cases.
Courtney et al. identified heart failure, coronary artery disease (CAD),
hepatic cirrhosis or chronic obstructive pulmonary disease to be predictive
of delayed complications (after more than 24 hours), in a review of more
than 1,000 TJA patients. Based on this review, they determined that
presence of any one of these risk factors increased the risk of postoperative
complications from 3.1% to 10%.31
A recently published “Outpatient Arthroplasty Risk Assessment” (OARA)
score to determine suitability of the patients for OTJA, takes into account
nine comorbidities and has a total of 61 points for assessment.28 Preoperative
optimization of patient health and the support of a dedicated caregiver in
the postoperative period were found to correlate with better results after TJA,
as evidenced by Berger et al. in a review of 5,373 total joint arthroplasties
conducted between 2004 and 2013.32
PATIENT EDUCATION AND SOCIAL OPTIMIZATION

Once a patient has been selected for an OTJA program, he/she should
participate in the institutional joint replacement education program along
with the person primarily responsible for caring for the patient at home
after discharge. A good prehabilitation program is the bedrock on which a
good rehabilitation is going to happen after discharge. The prehabilitation
program aims to walk the patient through the whole procedure of daycare
arthroplasty, emphasizing what role the patient is expected to play at
every juncture. This makes the patient an equal partner in his own care. It
attempts to familiarize the patient with the issues and challenges likely to be
encountered at home after discharge and how to tackle them. All attempts
are made to prepare the patients mentally, physically, and environmentally
for surgery so that they can mobilize faster postoperatively and stay ahead
in physical therapy rehabilitation.
Some patients might feel a little rushed getting discharged on the same
day and they might have concerns about medical help in the postoperative
period. They should be assured about the feasibility, safety, and efficacy
of the same-day discharge and should be given pamphlets explaining the

whole perioperative pathway along with detailed information and numbers
of contact person in the postoperative period.
The prospect of recovering in a more hospitable environment and having
a good night’s sleep away from the intrusive environment of an intensive
care unit (ICU) with its continuously beeping monitors and disturbances
because of activities of nurses and other patients. Sleeping on their familiar
beds and using their own washroom facilities can alleviate the stress related
to surgery and postoperative period enormously.
The patient should be adequately counseled by the whole team about
the practical challenges they might face while recovering at home and it
is always advisable that at such times the patient is accompanied by the
primary caregiver at home.
Most of the success of an outpatient program starts in the office. When
patients’ expectations are met with their surgeons’ expectations, the results
change and improve regarding admissions. If a patient is expected to get
up and ambulate on the same day as surgery, most of the time they will
accomplish that goal. One of the keys to that success is reiterating your
desires and goals for patients with the nursing staff and physical therapy
teams.
INTRAOPERATIVE CONSIDERATIONS
It is imperative to have a protocol-based anesthesia and pain management
pathway to have a successful OTJA program. This should ideally be
designed by all the stakeholders involved in caring for the patient. It should
incorporate valuable inputs from the surgeons and the pain physicians, in
addition to the anesthesiologists and physiotherapists. The aim is to have a
smooth postoperative course with minimal incidence of nausea, vomiting,
and giddiness, so that early mobilization can be achieved to facilitate the
same day discharge.
ANESTHESIA
Both general anesthesia (GA) and regional anesthesia are acceptable for
daycare arthroplasty.33 Though initial studies showed a decreased LOS and
decreased complication rate with the administration of a general anesthetic34
recent studies favor regional anesthesia.35
Continuous femoral nerve blocks (CFNBs) are the gold standard for pain
relief in TKAs and UKAs, but they have a variable amount of effect on motor
function in the postoperative period. As, in adductor canal block, motor
function is relatively preserved, it is favored for providing postoperative
analgesia in cases of knee arthroplasty. Spinal blocks with short-acting drugs
like lidocaine or ropivacaine, are effective for THA. This ensures minimal
incidence of sedation, nausea, vomiting, and pruritus, which are usually

associated with opioid additives.36
Local infiltration anesthesia (LIA) in the capsule and surrounding
soft tissues goes a long way in helping manage pain in the postoperative
period. Injected “cocktails” usually consist of a mixture of nonsteroidal anti-
inflammatory drugs (NSAIDs), in addition to local anesthetics. Liposomal
bupivacaine injection, wherever available may be used for infiltration to
provide long-lasting analgesia.
Infiltration between the popliteal artery and posterior capsule of the
knee (IPACK) block, a newer ultrasound-guided modality, is rapidly gaining
popularity for providing excellent postoperative analgesia in TKAs. It was
initially developed by Dr Sanjay Sinha at the University of Connecticut. In
this block, 20 mL of 0.2% ropivacaine is infiltrated between the posterior
capsule of the knee and the popliteal artery under ultrasound guidance
along with the liberal periarticular injection of local anesthetic by the
surgeon. The IPACK in conjunction with adductor canal block facilitates
earlier mobilization consequent to excellent analgesia. It seems to be the
order of the day for OTJAs in times to come. Care must be taken in the
postoperative period to maintain adequate fluid status and avoid postural
hypotension which may prevent early postoperative mobilization, essential
for discharge.
Blood is a noxious stimuli and as such all efforts must be made to
minimize intraoperative blood loss, both to prevent postoperative anemia
and also to prevent hemarthrosis causing significant postoperative pain
leading to poor progress with physical therapy.37
It is recommended to release the tourniquet and coagulate bleeders
before infiltration of liposomal bupivacaine or analgesic cocktails and
closure of the wound. Relative hypotension induced during regional
anesthesia helps in reducing blood loss in knee and hip arthroplasty.38,39
Tranexamic acid (TXA) helps in minimizing blood loss during TJA
without any significant rise in thromboembolic complications.40,41 Excessive
blood loss will delay timely discharge from the hospital.
SURGICAL TECHNIQUE
Minimally invasive and muscle-sparing surgical techniques have been
reported in most of the OTJA publications.9,11,13,18 However, OTJA has also
been successfully achieved using conventional surgical procedures.19,42,43
Kinematic alignment of knee implants using robotics seems to help in
faster recovery.44 They may have a role in daycare surgery, though, in the
absence of studies detailing long-term outcomes, it would be premature to
outrightly advocate their use. It is advocated to use subcuticular stitches and
tissue adhesives to effectively prevent wound oozing, thereby achieving a
reduced LOS.45-47 Minimally invasive surgical techniques, secure hemostasis

and sound wound closure, play a very important role in fast postoperative
recovery.
ANALGESIA
A good postoperative analgesia protocol with minimal side effects is the
bedrock of an OTJA. A multimodal protocol consisting of nerve blocks
and/or local anesthetic infiltration with or without adjuvant, given in the
immediate preoperative or intraoperative period establish foundation of
seamless and effective postoperative pain management.
An effective management of pain starts in the early preoperative period.
Some of the drugs are started at home before admission and then continued
during the perioperative period.48
A good number of patients are on drugs like paracetamol, gabapentins,
Cyclooxygenase-2 (COX-2) inhibitors, etc. on a regular basis for aches and
pains and these drugs are accordingly continued postoperatively as part of
multimodal analgesia.49,50
The nerve blocks and infiltration of analgesic cocktails in the operating
room continue to provide effective analgesia during the postoperative period
potentiated by oral drugs. These oral drugs are continued after discharge at
home as per protocol.
DEEP VENOUS THROMBOSIS PROPHYLAXIS

A patient-specific deep venous thrombosis (DVT) prophylaxis is provided
to all the patients. Patients with low DVT risk are managed using
nonpharmacological methods like early mobilization, adequate hydration,
compression stockings, or devices providing an intermittent pneumatic
compression (IPCD). High-risk patients with past thromboembolic event
also need pharmacological prophylaxis with drugs like aspirin, low-
molecular weight heparins (LMWH), coumarins, or rivaroxaban.
American College of Chest Physicians and American Academy of
Orthopaedic Surgeons have advocated use of aspirin, LMWH, or coumarin
for low-risk patients.51,52 However, a recent study has found no difference
in venous thromboembolism (VTE) among groups receiving aspirin or
LMWH.53 Even though rivaroxaban has been acclaimed a better agent
against VTE, bleeding complications remain a cause of grave concern.54
There is yet no agreement on drug of choice for thromboprophylaxis.
POSTDISCHARGE CARE
The patient is discharged after he has reasonably met all protocolized
discharge criteria and is comfortable. He should not be having any nausea
or vomiting or giddiness and the pain should be easily manageable on oral

medications. It is desirable to have the patient’s attendant present during
the discharge and use must be made of this opportunity to repeat all the
instructions regarding care at home, to discuss issues and scenarios that
might crop up and how to address them. A handout having all-important
contact numbers must be made available to the patient at this time.
A member of the primary care giving team needs to check on the patient
at his home after discharge to check on the wound status and to take care
of any other issues that may crop up. Telephonic follow-up with the patient
is continued over the next few days and feedback from the physiotherapy
and rehabilitation team working with the patient at his home is sought.
A follow-up visit to the hospital is scheduled as per the surgeon’s
protocol.
THE INDIAN PERSPECTIVE

Although TJA protocols in India have undergone a sea change over the past
decade with most high volume centers moving toward fast-tracking patients
thereby decreasing LOS without compromising the safety, there is yet only
one reported case of TKA with same-day discharge.
Challenges specific to OTJA in the Indian context pertain to patient
characteristics and logistics. Our patients are more likely to present with
advanced osteoarthritis as a result of the delay in seeking treatment
secondary to lack of proper awareness, fear of surgery, lack of motivation,
lack of insurance coverage, and financial constraints. They are also more
likely to have sought and tried alternative modalities of treatment for
many years with variable relief before finally coming over for surgery,
thereby presenting at a stage of relatively greater functional disability,
potentially rendering them ineligible for TJA on an outpatient basis. In
addition, our population is more likely to present with poorly controlled
(compliance issues) or undetected comorbidities, thereby being at risk for a
greater LOS.
Despite changes in the social environment with a drift toward nuclear
family model, most if not all of our patients may have somebody at home to
care for them, making them suitable for OTJA if other criterion is met. One
of the main things to be factored into an OTJA program is the geographical
distance of the patient from the treating center and the ability of medical
help to reach out to the patient, if required. In this regard, the lack of a
well-developed rapid emergency response system in our country presents
a formidable roadblock.
CONCLUSION
The transition to performing daycare total joint replacements is an evolving
process. It requires development of multidisciplinary integrated care
pathways from admission to discharge, keeping the ultimate goal in mind.
Institutions which have well-developed ERAS protocol have managed to
reduce the LOS, thereby making OTJA a reality.
Currently, OTJA is offered to healthy patients having a good “at home
support system” who are medically optimized to the fullest and are made
partners in their own care by prehabilitation. These patients benefit from
improved surgical techniques and better anesthesia and pain management
protocols, thereby meeting the goal of the same day discharge. This is
possible only through a dedicated investment of time and resources.
Several challenges lie ahead on the organizational front, and on safety
and economic fronts that need to be overcome before “daycare total joint
arthroplasty” can be outrightly recommended and gains wider acceptability,
more so in the Indian scenario. In order to avoid an increase in the rates
of complications and readmissions, only institutions with already running
“fast-track program”, should embark on an OTJA program as a logical extension.
KEY POINTS
• Demand for total joint arthroplasty is rising due to increase in aged
population.
• Reduced length of stay in hospital ensures optimum utilization of
resources.
• Enhanced “fast-track” recovery after surgery protocol facilitates safe
daycare arthroplasty.
• Proper selection and recruitment of patients is of paramount importance.
• Patient education and explaining detailed perioperative pathway go a long
way in patient comfort and satisfaction.
• Protocol-based anesthetic technique and impeccable pain management
avoiding adverse reactions like nausea, giddiness, etc. ensure early
mobility.
• Fast and minimally invasive surgical techniques, secure hemostasis,
sound wound closure, and blood management ensure a safe outcome.
• Teamwork involving anesthesiologist, surgeon, physician, physiotherapist,
nurses, paramedics, and home caregiver is the key to success.
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Experience From the First 15 Years. Instr Course Lect. 2016;65:547-51.
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45. Krishnan R, MacNeil SD, Malvankar-Mehta MS. Comparing sutures versus
staples for skin closure after orthopaedic surgery: systematic review and meta-
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46. Coulthard P, Esposito M, Worthington HV, et al. Tissue adhesives for closure of
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48. Halawi MJ, Grant SA, Bolognesi MP. Multimodal analgesia for total joint
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49. Munteanu AM, Florescu SC, Anastase DM, et al. Is there any analgesic benefit
from preoperative vs. postoperative administration of etoricoxib in total knee
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randomized controlled trials. Sci Rep. 2016;6:23726.
CHAPTER
18 Anesthesia for Neurovascular

Procedures
Neetu Jain, Bhuwan Chand Panday
INTRODUCTION
There is a multitude of vascular anomalies found in the central nervous
system (CNS) which are potentially life-threatening and require elective or
emergent intervention. Though several types of lesions have been described,
there are two main types of neurovascular abnormalities; aneurysm and
arteriovenous malformation (AVM). Enlargement of these lesions may cause
symptoms due to compression of adjacent structures while bleeding from
the lesions is potentially life-threatening and requires intervention. Multiple
parameters have been described to evaluate the risk of bleeding in these
vascular lesions. State of art imaging technology provides precise diagnosis
and aids in planning management of these lesions. The choice of craniotomy
with clipping or coil embolization may be decided based on type of lesion,
availability of infrastructure, and discussion with patient and family. Newer
surgical techniques and evolvement of interventional neuroradiology (INR)
with good perioperative anesthetic management has improved the clinical
outcome of complex neurovascular lesions. Still, there is a significant
disability, morbidity, and mortality associated with management of these
patients. In this chapter, we shall discuss the anesthetic management of
intracranial aneurysmal clipping, resection of AVMs, and interventional
radiologic treatment of various neurovascular lesions.
INTRACRANIAL ANEURYSMS
The incidence of intracranial aneurysms is 0.2–9.9% in general population.1
All aneurysms do not rupture. The ruptured intracranial aneurysm presents
as subarachnoid hemorrhage (SAH) and has an incidence of 6.1 per 100,000
person-years.2 The ruptured intracranial aneurysms account for 85% cases
of nontraumatic SAH. Only 5% of all cerebrovascular accidents are due to
SAH but it is associated with high morbidity and mortality. Twelve percent
patients die before reaching the hospital while in-hospital mortality at
1 month is 35–40%. Majority of the remaining survivors have a high
dependency rate (33%) or suboptimal quality of life.
Anesthesia for Neurovascular Procedures 257
Table 1: Risk factors for subarachnoid hemorrhage (SAH).

Risk factors Example
Comorbidities Hypertension
Substance abuse Smoking, alcohol, cocaine, ecstasy
Genetic and collagen Ehlers Danlos type IV syndrome, Marfan’s syndrome,
disorders polycystic kidney disease, fibrous dysplasia,
neurofibromatosis type I disorder
Others Pregnancy, oral contraceptive pills
Fig. 1: Circle of Willis with incidence of various aneurysms.
Risk Factors
The common risk factors associated with development of aneurysm are
enlisted in Table 1. There has been a steady decrease in the incidence of
SAH with a decrease in the prevalence of hypertension and smoking.2
Cerebrovascular Anatomy and Site of Aneurysm

Aneurysms typically occur at arterial branch points of cerebral vasculature.
The most common site of aneurysm is anterior communicating artery (35–
40%) and middle cerebral artery (30–35%). Incidence of aneurysm at the
junction of posterior communicating artery and anterior choroidal artery is
20–25% while the incidence is 5–10% at bifurcation of basilar artery (Fig. 1).
About 33% patients have multiple aneurysms.3 Ruptured aneurysm usually
presents at the age of 55–60 years. SAH is more common in females as
compared to males in the ratio of 2:1.
Circle of Willis
The circle of Willis is formed by bilateral internal carotid arteries (ICA)
anteriorly, and two vertebral arteries posteriorly that anastomose at base
of skull to form a circle. Anatomy is variable in patients and it forms
an important source of collateral circulation in case of ischemia due to
compromised blood supply to a part of brain.
Ipsilaterally, ICA after entering the skull branches off as ophthalmic
artery followed by the posterior communicating artery. After branching off
the anterior choroidal artery, the ICA bifurcates into anterior cerebral and
middle cerebral artery (MCA). Usually, MCA lacks good collaterals and is
prone to ischemia. Posteriorly, the two vertebral arteries anastomose to
form basilar artery. The basilar artery bifurcates into two posterior cerebral
arteries which anastomose with ICA by posterior communicating arteries
to form the circle of Willis
The risk of rupture of aneurysms is dependent on its size and location.
• Size: Less than 10 mm. Less likely to rupture as compared to 10–24 mm
in diameter. Rebleeding is also more frequent if aneurysm size is more
than 10 mm.
• Location: Aneurysms located in posterior circulation, i.e. vertebrobasilar
or basilar tip have a higher propensity to rupture.4
• Strength of aneurysm wall: Related to collagen type and reticular fiber
in medial layers of arteries.5
• Familial history: History of aneurysm rupture in the family.
• Transmural pressure gradient (TMPG): Difference between pressure
inside, i.e. arterial blood pressure (ABP) and outside, i.e. intracranial
pressure (ICP) the aneurysmal wall. Any factor that increases the arterial
BP (intubation, sympathetic stimulation) or leads to sudden fall in ICP
[opening of cerebrospinal fluid (CSF) drain] can lead to increased
chances of rupture.
Clinical Presentation
Intracranial aneurysm may be asymptomatic and discovered incidentally
on imaging. Incidental aneurysms have an annual rate of rupture of 0.76%.6
Large aneurysms may cause focal symptoms due to mass effect especially
in case of ICA and posterior circulation aneurysm.
Ruptured aneurysms usually cause SAH which presents as worst
headache of one’s life described as hammer blow. Patients may have sentinel
headaches days or weeks prior to rupture in 40% of cases. The headache
may be associated with nausea, vomiting, lethargy, diplopia (due to III nerve
palsy), focal neurological deficits, altered sensorium or loss of consciousness.
Patients may present with seizure in 25% of cases.
Table 2: Specific features of intracranial aneurysm.

Site of aneurysm Clinical features
Anterior communicating artery Memory disturbance, confabulation,
paraparesis, personality changes
Posterior communicating artery Third nerve palsy
Intercavernous internal carotid Cranial nerve deficit from II to VI alone or
artery in combination, progressive visual loss, facial
pain retro-orbital pain
Posterior circulation aneurysms Intraventricular hemorrhage, hydrocephalus,
brainstem dysfunction
Table 3: Hunt and Hess classification of patients with intracranial aneurysm.

Grade Clinical features
1 Asymptomatic, mild headache
2 Moderate-to-severe headache, nuchal rigidity, no focal deficit other than
cranial nerve palsy
3 Mild mental status change (drowsy or confused), mild focal neurologic deficit
4 Stupor, or moderate-to-severe hemiparesis
5 Comatose, or decerebrate rigidity
Table 4: World Federation of Neurological Surgeons grading for intracranial aneurysm.

Grade Glasgow coma scale score Neurological deficit
1 15 No motor deficit
2 13–14 No motor deficit
3 13–14 Motor deficit present
4 7–12 Motor deficit may be present or absent
5 3–6 Motor deficit may be present or absent
Patient may also present with sign of meningism like neck stiffness or
photophobia. Fundoscopic examination may reveal papilledema or retinal
hemorrhages. Clinical presentation of specific intracranial aneurysms is
described in Table 2.
Severity of Subarachnoid Hemorrhage

The severity of SAH can be clinically assessed and graded using Hunt and
Hess classification (Table 3) or the World Federation of Neurosurgeons
Scale (WFNS) (Table 4). Both these classifications have been used for
Table 5: Fisher scale based on computed tomography (CT) appearance for subarachnoid
hemorrhage.
Grade Description
1 No blood
2 Diffuse deposits of subarachnoid hemorrhage (SAH) blood, no clots, no
layers of blood >1 mm thick
3 Local clots or vertical layers of blood ≥1 mm thickness
4 Diffuse or no SAH, but intracerebral or intraventricular clot
prognostication and predicting the outcome. Higher grades are associated

with poor outcome. Another grading scale based on computed tomography
(CT) scan evaluation is the Fisher Grading Scale based on the extent of
intracranial bleeding which determines the risk of vasospasm (Table 5).
Systemic Manifestations of Subarachnoid Hemorrhage

Central Nervous System
Patient may have altered level of consciousness, cranial nerve palsy, visual
field defects, or motor and sensory neurological deficits. Initial assessment
using Glasgow Coma Scale (GCS) and clinical examination helps in grading
and assessing the severity of SAH and long-term prognosis. Common
neurological complications associated with SAH are:
• Rebleeding: The neurological condition may deteriorate because of
rebleeding. The risk of rebleeding is highest in initial 72 hours and
carries a very high mortality rate.
• Hydrocephalus: Hydrocephalus may develop in 25% cases of ruptured
aneurysms as blood enters the ventricles and blocks the flow of CSF.
• Delayed cerebral ischemia (DCI): Delayed cerebral ischemia due to
vasospasm commonly occurs 3–12 days after bleeding. If suspected
clinically, it can be confirmed by CT scan, transcranial Doppler (TCD)
or angiography. Radiological features of vasospasm are present in 60%
of patients with SAH. Clinically, it manifests in 10–40% of patients and
depends on volume of blood in subarachnoid space. Various strategies
to prevent and manage vasospasm are enlisted in Box 1.
• Seizures: Seizures develop in approximately 6.3–7.8% of patients of SAH.7
However, prophylactic epileptics are not advocated.
Electrocardiogram (ECG) changes in the form of ST-T wave changes,
QT prolongation, and U waves are seen in almost 80% of patients. With
Box 1: Management of vasospasm.

Preventive strategies:
•• Maintain euvolemia using isotonic crystalloids.
•• Blood pressure management:
–– Before aneurysm is secured: SBP < 160 mm Hg
–– After aneurysm is secured: SBP 140–180 mm Hg
•• Maintain CPP of 80–120 mm Hg.
•• Control ICP with osmotic therapy (3% hypertonic saline preferred over mannitol
for its renal sparing effect) or external ventricular drain.
•• Maintain Hb > 9 g%.
•• Nimodipine: 60 mg 4 hourly PO for 3 weeks.
•• Avoid hypoglycemia, dehydration, fever, hypoxia, hypocarbia, hypomagnesemia.
Therapeutic strategies:
•• Induced hypertension using norepinephrine, phenylephrine or vasopressin.
•• Intraarterial vasodilator therapy using nimodipine, milrinone.
•• Balloon angioplasty.
•• Intra-arterial stenting.
(CPP: cerebral perfusion pressure; ICP: intracranial pressure; SBP: systolic blood
pressure; PO: per os)
higher WFNS grade, SAH patients are more likely to develop arrhythmias,
hypertension, or ischemic myocardial dysfunction. These manifestations
are due to direct injury to posterior hypothalamus that leads to excessive
catecholamine release. These changes reflect severity of neurological injury
but are reversible in most of the cases.8
Respiratory System
Many patients presenting with SAH have a history of smoking and may be
suffering with its ill-effects. They are also predisposed to atelectasis and
aspiration pneumonia due to reduced level of consciousness and prolonged
bed rest. Patients may develop neurogenic pulmonary edema due to massive
sympathetic discharge. This reflects severity of subarachnoid bleed and is
an indicator of poor outcome.9
Fluid and Electrolyte Imbalance

Volume depletion may develop because of poor intake, diabetes insipidus
(DI), or syndrome of inappropriate secretion of antidiuretic hormone
(SIADH). Hyponatremia is more frequently seen than hypernatremia
and may be due to cerebral salt wasting syndrome (CSWS) or SIADH
and is associated with longer hospital stay.10 Hypernatremia may occur
iatrogenically due to mannitol or hypertonic saline (HS) infusion.11 Less
frequently, hypernatremia may be due to DI which most likely develops
due to hypothalamic ischemia. Hypothalamic ischemia may happen due to
decreased cerebral perfusion pressure (CPP) or vasospastic involvement of

anterior cerebral artery and anterior communicating artery distribution.12
Hypernatremia is independently associated with adverse outcome and
mortality.13
Management Modalities
Intracerebral aneurysm may be amenable to surgical clipping or endo
vascular treatment (EVT). There has been substantial increase in popularity
of endovascular intervention after the International Subarachnoid Aneurysm
Trial (ISAT) proved advantage of endovascular coiling over surgical clipping
in terms of disability-free survival at 1 year.14 However, sac recanalization
occurs in 12.4% of aneurysms after EVT in long term. Therefore, EVT is
effective for prevention of long-term bleeding, but patients require to
follow-up for 10 years or more in aneurysms larger than 10 mm size.15
Anesthetic Management of Surgical Clipping

Patients presenting with SAH may have altered level of consciousness, focal
neurological deficits, and sequelae of sympathetic overactivity leading to
hypertension and cardiovascular manifestations. Owing to SAH, their
cerebrovascular reactivity and cerebral autoregulation may be impaired and
therefore, the CPP becomes dependent on mean arterial pressure (MAP).
Cerebral perfusion pressure (CPP) = mean arterial pressure (MAP) –
intracranial pressure (ICP).
In these cases, in order to maintain adequate CPP, manipulation of MAP,
and ICP will be required. But, a sudden increase in MAP and/or a sudden
fall in ICP can cause sudden changes in TMPG across the wall of aneurysm
and risk its rupture. So, the anesthetic goal is to maintain a fine balance so
as to maintain CPP and TMPG across the wall of aneurysm in a safe range.
Preoperative Evaluation and Anesthetic Plan

A detailed medical history and clinical examination can give useful insight
into the current medical condition of the patient. In relation to a case of
ruptured intracranial aneurysm, when only limited time is at hand for
optimization, clinical assessment is indispensable for risk assessment and
prognostication as per exiting comorbidities and current neurological status
with its sequelae. It is important to know the premorbid functional status
to assess the cardiac reserve. The long-term history and overall control of
blood pressure and glycemic status will help in ascertaining the anesthetic
goals for that particular case. Previous history of asthma, chronic obstructive
pulmonary disease, renal impairment, smoking, alcohol, and drug abuse
can aid in planning anesthetic and postoperative management. Routine
laboratory investigations including complete blood count, coagulation

profile, blood type and screen, and metabolic panel should be available.
ECG may show changes and echocardiogram should be done. Radiological
investigations include CT scan which determines the extent of bleeding
and risk of vasospasm based on Fisher Grading Scale (Table 5). Further, CT
angiography, magnetic resonance angiography (MRA), or digital subtraction
angiography (DSA) determines the details of size, location, and configuration
of aneurysm.
Surgical clipping may be indicated in aneurysms with very difficult
angiographic anatomy, e.g. very wide-neck aneurysms, vessels arising from
or in close relation to neck of aneurysm, or associated large hematoma.
Informed consent should be obtained from patient and/or family after
proper counseling and discussion of treatment modalities in detail.
Communication with the surgeon aids in planning the anesthetic and
improves the teamwork output in case of emergency clinical situations. It
should include:
• Patient positioning
• Surgical anatomy and plan of temporary aneurysm clipping
• Anticipated blood loss
• Blood pressure goals and plan for intraoperative rupture
• Brain relaxation techniques and management of spinal drain.
Preoperative Stabilization and Transport

Patients with ruptured aneurysms are usually managed preoperatively
in neurocritical care unit. Patients with raised ICP may be sedated and
electively ventilated with aim to maintain PaCO2 of 30–35 mm Hg and
PaO2 of 100 mm Hg. Hemodynamic management should aim to maintain
adequate CPP. As per current recommendations, “3H” therapy has fallen out
of favor.16 Currently, the focus is on maintaining euvolemia and controlled
hypertension with a systolic blood pressure of 120–160 mm Hg before
aneurysm is secured. Transport of these patients may be associated with
hemodynamic instability due to sympathetic stimulation and rise in ICP.
Therefore, adequate attention should be paid to hemodynamic monitoring,
sedation, and ventilatory management of intubated patients during hospital
transfer. Also, patients with ventriculostomy should be transferred with
CSF drains closed to avoid intracranial hypotension which can cause acute
rebleed due to increase in TMPG.
Induction
Besides standard anesthesia monitoring, ABP monitoring is established
prior to induction to facilitate smooth hemodynamic control during
induction and intubation. A wide bore intravenous (IV) access is secured.

A central venous catheter may be inserted based on patient’s medical
history, for administration of inotropes and for transfusion due to major
blood loss. Neuromonitoring techniques like electroencephalography (EEG)
and evoked potential monitoring may be used for aneurysm clipping but
their role in patient outcome is uncertain. Somatosensory-evoked potential
(SSEP) monitoring may be used for monitoring anterior circulation, SSEP,
and brainstem auditory-evoked potential (BAEP) for monitoring posterior
circulation, and motor-evoked potential (MEP) monitoring for middle
cerebral and basilar arteries.
Induction of anesthesia is usually done with thiopentone or propofol
in a controlled and smooth manner to avoid any hemodynamic instability.
Thiopentone decreases cerebral metabolic rate for oxygen (CMRO2),
cerebral blood flow (CBF), and ICP. MAP is also reduced with thiopentone
but CPP is maintained as fall in ICP is more than fall in MAP. A significant
reduction in CPP can occur when propofol is administered for induction
and dose should be titrated to clinical effect. Ketamine increases CMRO2,
CBF, and ICP and should be avoided in these patients. Hypertension and
hypotension should be avoided during induction, intubation, surgical pins
application, incision and opening of dura as hypertension is associated
with risk of rupture of aneurysm while hypotension may compromise CPP.
Intravenous lignocaine, fentanyl, esmolol, or labetalol may be used to blunt
the sympathetic response. Phenylephrine or noradrenaline may be used to
treat hypotension.
A sudden decrease in ICP should be avoided before opening of dura as
it may lead to increase in TMPG leading to rebleed. Therefore, spinal drains
should not be opened before opening of dura. Intravenous mannitol 20%
in a dose of 0.25–1 g/kg may be given over 10–15 minutes as this does not
cause any acute changes in TMPG. Alternatively, hypertonic saline (HTS)
may also be used to control ICP.
Maintenance
Anesthesia may be maintained with inhalation agents like isoflurane,
sevoflurane, or desflurane using ≤ minimum alveolar concentration (MAC)
as cerebral vasodilatory effects are insignificant at this concentration.17,18
Propofol in the form of total intravenous anesthesia (TIVA) or in combination
with inhalation agents may be used. No one technique has been found
to be superior to other in terms of neurological recovery.19 Nitrous oxide
should be avoided. Opioids like fentanyl can be supplemented to reduce the
stress response. Muscle relaxation may be achieved with a nondepolarizing
muscle relaxant which may be use as a continuous infusion to prevent any
sudden movement.
Intraoperatively, normothermia should be maintained. A targeted

temperature management (TTM) of 36.5–37.5°C should be aimed for.20
Hyperglycemia is associated with poor outcome. Blood glucose levels
between 80 mg/dL and 180 mg/dL should be maintained. Euvolemia and
plasma oncotic pressure should be maintained. Serum sodium levels should
be kept in high normal range. Hemoglobin should be maintained >10 g%
to prevent vasospasm.21
Brain Relaxation
The importance of brain relaxation cannot be overstated in aneurysm surgery
as it facilitates exposure and decreases the traction required on retractors. In
all intracranial surgeries, neck should be kept in neutral position with head-
end elevation to prevent jugular venous compression. Hypercarbia should
be avoided and a low normal PaCO2 of 30–35 mm Hg should be aimed
for. Adequate depth of anesthesia should be maintained and an additional
dose of fentanyl or IV anesthetic may be required at time of surgical frame
application, incision and opening of the dura. Decongestants like mannitol
or hypertonic saline may be required. Controlled CSF drainage through
ventriculostomy catheter may facilitate reduction of ICP. Lastly, decrease
in CMRO2 by barbiturate boluses may be required.
Temporary Clipping
Temporary clips are placed on feeding artery proximal to aneurysm
to facilitate dissection, excision, and arterial reconstruction. Low BP is
desirable during application of temporary clip. Thereafter, BP may be
raised to promote collateral perfusion to ischemic area. Clipping time
should preferably be limited to <10 minutes. Clipping any intracranial
artery for >20 minutes puts the patient at risk of ischemia.22 Temporary
clipping is associated with a period of focal cerebral ischemia and multiple
methods have been suggested to preserve brain viability. Burst suppression
on EEG using thiopentone or propofol is the most commonly practiced.
Intraoperative hypothermia has also been suggested as a protective measure
but did not affect the outcome in patients who had a temporary occlusion.23
Confirmation of Surgical Clipping

After permanent clipping, normal to supranormal BP is desired. Correct clip
placement may be confirmed by applying Doppler ultrasound directly to the
feeding vessels and confirming adequate blood flow proximally and distally
while aneurysm is excluded. Near-infrared indocyanine green angiography
technique is also commonly used. Modification of clip placement may be
done if desired. Intraoperative angiography or postoperative DSA may be
used as a confirmatory method for adequate occlusion.
Intraoperative Aneurysm Rupture

The risk of intraoperative aneurysm rupture remains from induction until
clipping and rebleeding is associated with a very poor outcome and high
mortality. Risk factors for rupture include poorly controlled hypertension,
coronary artery disease, and chronic obstructive pulmonary disease.24
An increase in aneurysmal TMPG increases the risk of rupture. Increase
in TMPG may be caused by rise in MAP (during intubation, pinning,
positioning, incision or dural opening) or sudden fall in ICP (rapid infusion
of mannitol, hyperventilation, rapid CSF drainage prior to dural opening).
If aneurysmal rupture occurs while aneurysm is exposed, bloodless field
facilitates in rapid clipping. This is done by inducing hypotension using
esmolol and reducing CMRO2 with propofol by achieving burst suppression.
After clip is successfully placed, blood and volume resuscitation may be done.
If aneurysm rupture is suspected before aneurysm exposure, by
unexplained increase in BP or ICP, the team should decide whether to
proceed with surgery or CT scan or angiography. Meanwhile, supportive
measures to optimize CPP and managing ICP should continue.
Emergence and Postoperative Course

In uncomplicated cases, smooth emergence and extubation immediately
postsurgery should be contemplated as it facilitates neurological assessment.
Hypertension, coughing, and straining on tube should be avoided.
Intravenous lignocaine 1 mg/kg facilitates smooth extubation as it depresses
cough reflex temporarily. Multimodal analgesia using paracetamol, opioids,
and scalp block is effective. Monitoring and postoperative care in immediate
postoperative period continues in neurocritical care unit. In patients with
cerebral edema, skull bone flap is removed and preserved in abdomen
for future cranioplasty. Such patients require elective postoperative
ventilation with sedation, monitoring, and serial neurological assessment
in neurocritical care unit. Postoperative CT scan may be required if there
is suboptimal neurological status.
Anesthesia for Endovascular Management of Aneurysm

Coil embolization for aneurysms and a variety of other procedures are now
commonly performed in INR suites. These procedures require high-resolution
fluoroscopy and high-speed DSA. EVT may be done for ruptured and
unruptured intracranial aneurysms. A patient with aneurysm may undergo
DSA followed by coil embolization. With advancement in technology, more
complex lesions have become amenable to EVT using stent-assisted coiling
or flow diverters. Patients may also require intraarterial vasodilator therapy
or angioplasty for management of vasospasm.
Digital subtraction angiography can usually be done under MAC unless

patients’ poor neurological status requires airway control. Coil embolization
is usually done under general anesthesia as it requires patient immobility.
Cases in neuroradiological suites is a challenge for an anesthesiologist
as it requires hemodynamic management, airway protection, immobility,
and monitoring of neurological status, with additional readiness for any
emergent situation that may arise in a remote location.25
Preanesthetic Preparation
Working in INR suite is associated with risk of exposure to ionizing radiation
and adequate radiation safety measures should be undertaken using lead
aprons and thyroid shield. Ergonomics should be taken into consideration
at time of design conceptualization of INR suite to enhance protection of
personnel and patient, as the high-resolution image intensifier requires
space for full range of movement. Use of lead screens with view of anesthesia
monitor and surveillance with thermoluminescent dosimeter (TLD) badges
should be done for personnel regularly working in INR suite. Intravenous
tubings, monitoring leads, and breathing circuit should be secured away
from radiography field using extensions as required.
Standard anesthesia monitoring and invasive blood pressure monitoring
is advocated to monitor beat to beat change in blood pressure. A large bore
intravenous access is secured. Patient is catheterized and input-output
monitoring is diligently done as significant amount of flush solution and
contrast medium may be used by interventionist.
Minimum Alveolar Concentration/General Anesthesia

In case of MAC, fentanyl along with sedative dose of propofol or
dexmedetomidine is advocated. General anesthesia has various advantages
over MAC as it provides completely still patient and facilitates controlled
hypertension, hyperventilation-induced decrease in ICP and better control
in case of catastrophe. Sympathetic response to intubation should be
monitored using ABP and controlled using esmolol, labetalol, fentanyl,
propofol, or lignocaine. Maintenance of anesthesia may be done with
TIVA or inhalation technique. Regular assessment of administered fluid
(intravenous fluid, fluid in pressure bags, and urine output) will guide the
intravascular fluid status. Temperatures in INR suite is usually kept low.
So, adequate precautions (warming blanket, warm fluid) are taken during
the procedure to avoid hypothermia. Arterial blood gas may be done to
assess the efficacy of ventilation and adequacy of perfusion. Ventilation is
maintained to keep the end-tidal CO2 at 30–35 mm Hg especially during
endovascular procedure when cranium is closed. Femoral arterial access
is usually used by the interventionist. The pulse oximeter probe can be

placed on the toe of the side of femoral puncture to detect embolus induced
decrease in saturation.
Anticoagulation
Coagulation should be monitored and managed to prevent thromboembolic
complications during procedure. Intravenous heparin 70 IU/kg is given
initially followed by intermittent boluses or infusion to protect against
thrombosis due to endothelial trauma and thrombogenicity of instilled
material. An orogastric tube may be placed to administer antiplatelet agents
like aspirin or clopidogrel especially in cases of stent-assisted coiling.
Intraprocedural Complications
• Aneurysm rupture during procedure may happen especially during coil
placement. It appears as a flush due to dye extravasation. Management
is done by reversal of heparin anticoagulation by protamine, hemo
dynamic management (maintaining low normal MAP), managing
ICP, and maintaining CPP. Endovascular sealing may be attempted.
If unsuccessful, procedure may be aborted and emergency CT and
ventriculostomy may be required.
• Downstream thromboembolism may be detected on angiography.
Management requires induced hypertension and administration of
abciximab, a glycoprotein IIb/III a receptor antagonist. Constant
communication between the interventionist and anesthesiologist is
required to successfully conduct the procedure.
Decision for extubation or elective ventilation depends on the patient
condition. Extubation is always done under controlled hemodynamic
conditions.
ARTERIOVENOUS MALFORMATION
Arteriovenous malformation is a complex vascular lesion which contains
abnormal connections between arteries and veins. Although the exact
pathogenesis is still not clear, it is believed to be due to the abnormal
angiogenesis during developmental phase of fetus or after birth.
Arteriovenous fistula is slightly different as it usually contains one artery
and vein. Fortunately, it is neither carcinogenic nor infectious. It can be
found anywhere in the body but common places are brain, spine, and
faciomaxillary region. Common intracranial site is supratentorial followed
by dural and infratentorial. Cases may be diagnosed incidentally or by
symptomatic presentation. Presentation of these cases may range from
mild symptoms to severe and life-threatening symptoms if affecting the

vital organs. Clinically significant symptoms are usually present due to
the enlarged lesions, hemorrhage, or stroke. Symptoms present as per the
site of lesion in the brain. Spinal AVM may lead to abnormal blood supply
which can cause impingement of nerve bundle due to hematoma or stroke-
induced decreased blood supply which can progress to limb weakness and
permanent disability. Radiographical features show a central nidus with an
intermingling of blood vessels with arteriovenous connection along with
absence of capillary network. The incidence of parenchymal bleeding is
high in cases of venous hypertension, which may be due to obstruction of
outflow.26 Interestingly, a few studies have reported change in size of these
lesions—decrease, increase, or remains the same but in some rare finding,
it may disappear.27,28 Recently, a study was conducted in 154 patients,
various parameters were analyzed and concluded with a very low incidence
(0.014%) of spontaneous obliteration of these AVM.29 Therefore, physician
must not wait or expect for spontaneous closing of these defects.
Incidence
The incidence of AVM varies according to the geographical location. In
China, the ratio of AVM to the aneurysm is similar (1:1),30 while in Singapore,
the incidence of AVM is four times (4:1) than the aneurysm.31 Though these
cases are rare and patients are asymptomatic in the population, it is difficult
to assess the demographical data in a specific population. Inclusion of only
symptomatic patients was considered as the most appropriate criteria to
evaluate the disease in a population. A well-structured study including only
symptomatic patients found the overall presence of AVM as 0.94 per 100,000
person-years. The overall incidence rate was found to be 10.3 per 100,000
population.32
Grading of Arteriovenous Malformations

The Spetzler-Martin grading system is widely used due to its simplicity to
grade the complex AVM lesions based on which management strategy is
planned (Table 6).33
The severity of AVM increases from grade I to grade V. Patients with
Grade V features suffered with maximum morbidity and mortality due to its
size and location at complex and crucial brain structures. A modification of
the above grading system based on the treatment plan is also used. As the
treatment for grades I and II, and grades IV and V is similar, the 5-tier system
is modified to 3 class system where grades I and II are clubbed together as
class A, grade III as class B, while IV and V form class C.34
Table 6: Spetzler–Martin grade of arteriovenous malformation (AVM).8

Features Points
Size of AVM
Small (<3 cm) 1
Medium (3–6 cm) 2
Large (>6 cm) 3
Eloquence of adjacent brain
Noneloquent 0
Eloquent 1
Type of venous drainage
Superficial only 0
Deep 1
Arteriovenous Malformations with Elevated Risk of

Bleeding and Rebleeding
The risk of hemorrhage in patients diagnosed with AVM has been evaluated
in few studies.33,35-37 Patients presenting with hemorrhage due to brain
AVM are prone to rebleeding. Hemodynamic perturbations might play an
important role. A deep lesion enhances morbidity, while posterior fossa
lesions are shown to have worse outcome than the supratentorial lesions.
Drainage of these malformations may be either into superficial or deep
venous system. Drainage into deeper veins is liable to have higher risk of
bleeding as compared to superficial veins. Multiple draining veins in the
outflow track decreases the congestion inside the AVM and so chances
of rupture are significantly low. In addition to these features, risk is also
associated with a number of feeding arteries and draining veins, i.e. higher
the number higher the risk. Presence of aneurysm elevates the risk of
bleeding. Micro-catheters were also used to monitor the arterial pressure
and found that the pressure was at the higher range after the hemorrhage
has taken place.38 It has been noted that pressure in small AVM was higher
than the large lesions.39 which means pressure and size are in inverse
relationship.40 Incidence of hemorrhages in small AVM defects is higher
than the large defects, possibly due to higher pressure in small defects.37
Clinical Features
Patients with AVM are usually asymptomatic until an event causes clinical
symptoms. In case of hemorrhage or enlarged size, there may be pressure
effects on the adjacent structures. Symptoms of these patients are due
to the region of the brain involved. Bleeding in the brain causes sudden,
severe headache, vomiting, neck rigidity, ringing of ears, and seizures.
AVM bleeding in the spine may lead to severe backache, limb weakness,
or paralysis of the limb.
Diagnosis
Newer and advanced imaging system provides very minute details of this
complex lesion.41 Other lesions similar to AVM (e.g. vascular malformation),
which are otherwise difficult to diagnose can be well differentiated with
the help of these modalities. Neuroradiological imaging system plays an
important role in diagnosing associated risk factors with AVM lesion,
detailed analysis of nidus size, aneurysm and presence of multiple arteries
and outflow venous system. Depth and location of the nidus, deep venous
drainage are all important features which play a crucial role in managing
these patients.
In the classical brain AVM, there is direct transition from artery to vein
(due to absence of capillary bed) in a place called nidus. Nidus of this defect
can be divided into two types: (a) glomerular; and (b) diffuse.
Commonly used imaging systems are CT scan, magnetic resonance
imaging (MRI) and angiography. DSA is another sensitive tool with high
speed and high-resolution images to detect and analyze small vascular
defects.42 Using these advanced tools, details of feeding arteries, drainage
veins, size, and location of nidus can be seen. For assessment of AVM and
its improved and advanced analysis, the potential advantages of TCD and
3D hemodynamic mapping have been emphasized.43
This information facilitates grading the severity of the disease and
provides a roadmap of risk assessment, chances of rebleed, management
strategy, and long-term prognosis.
Management Strategies
There are three management strategies described in the literature. It can be
used alone or in combination, depending on AVM lesion.
Microsurgical Resection
Surgical excision of brain AVM is possibly the gold standard treatment
for this malformation. A combination of treatment modality may be used
for removal of complex lesions. In difficult location and in cases of highly
vascular structures, prior embolization helps to decrease bleeding. Brain
AVM requires craniotomy for adequate exposure to isolate arterial feeder,
nidus and venous outflow from the normal parenchyma. Though it provides
complete cure of the disease, there is some disadvantage as well, e.g. risk
associated with an invasive procedure, long recovery time.
Radiosurgical
Radio intervention is best suited in patients with high surgical risk, therefore,
it is advocated for small to medium size AVM, deeper lesions and those
located close to eloquent brain areas. Majority of cases achieve obliteration

of AVM flow, but due to high-intensity radiation, probability of radiation-
induced adverse effect is always there. The obliteration of flow is not instant
and so the possibility of bleeding is always there during latent period.
Endovascular Treatment
State of the art gadgets with high-resolution imaging technology provides
images in real-time. The aim of endovascular treatment is to stop blood
flow to this defect. Neurointerventionist uses various methods to facilitate
embolization and obliterate blood flow. Embolization can be achieved
with coils, glue (N-butyl-2-cyanoacrylate), ethylene vinyl alcohol polymer
(Onyx) or polyvinyl alcohol (PVA) particles. These materials are placed at
the target site under high-resolution fluoroscopy. Once thrombosis sets
in, blood flow is dramatically reduced (Figs. 2 and 3). Even this advanced
technique is not without risk and complications are reported like migration
of embolizing agent and occlusion of distal venous circulation or pulmonary
hypetension.44
Anesthesia Considerations
All the parameters must be evaluated in details (hemodynamics, system
evaluation, radiological assessment, investigations, comorbidity) for risk
evaluation. The plan of management is decided after evaluation, discussed
with multidisciplinary team and patient is counseled. Optimization of
elective cases is preferred. These procedures can be conducted under
local, MAC, or general anesthesia. AVM surgery can be conducted under
Fig. 2: Pre-embolization angiography. Fig. 3: Postembolization angiography.

local anesthesia where functional testing is advocated.45 The anesthetic

management is on the lines of management of intracranial aneurysm.
Salient features of anesthetic management of AVM will be discussed here.
• Excision of AVM may be technically difficult and fraught with risk of
significant hemorrhage despite preoperative embolization.
• Management in the postoperative period is very crucial. Controlled
hypotension, regular neurological assessment, nonsedative analgesics
with optimum fluid administration lead to good outcome.
• After the excision of AVM lesion, there is sudden increase in blood flow
in the adjacent tissue which is known as normal perfusion pressure
breakthrough (NPPB) which can be avoided with controlled hypotension46
(labetalol infusion), mannitol or hypertonic saline and dexamethasone.
• Large amount of dye is used to conduct these procedures leading to
a considerable risk of contrast-induced nephropathy (CIN). N-acetyl
cysteine 600 mg twice a day may be given pre- and postembolization
to reduce the risk. Relevant blood investigations can detect the changes
at the initial stage, e.g. creatinine, urea, and electrolytes and facilitate
early management.
ENDOVASCULAR THERAPY FOR OTHER PROCEDURES

With advancement of INR, a variety of conditions are amenable to endovascular
treatment. Common conditions treated by INR with their anesthetic
considerations and interventions required are enumerated in Table 7.47
Table 7: Prophylactic precautions and intervention for various neuroradiological

procedures.
Lesion Intervention Rationale for intervention
1. Intracranial AVM Deliberate hypotension Avoid NPPB
2. Dural AVM Deliberate hypercapnia High venous flow decreases risk
of embolic material embolization
3. Extracranial AVM Deliberate hypercapnia High venous flow decreases risk
of embolic material embolization
4. C
arotid cavernous Deliberate hypercapnia Postprocedure NPPB
fistula
5. E
thanol sclerotherapy Avoid nitrous oxide, Brain and airway swelling,
of AVM prophylactic measures hypoxemia, hypoglycemia,
to decrease ICP, anti- cardiorespiratory arrest
inflammatory agents
6. Acute stroke Maintain perfusion Avoid ischemic infarct
pressure, neurological
assessment
7. B
alloon angioplasty of Maintain higher Cerebral ischemia
cerebral vasospasm due perfusion pressure
to aneurysmal SAH
(AVM: arteriovenous malformation; ICP: intracranial pressure; NPPB: normal perfusion
pressure breakthrough; SAH: subarachnoid hemorrhage)
CONCLUSION
With advancement of technology and new innovations, patients with
more complex lesions are presenting for neurovascular surgery and
endovascular therapy. Proper and timely communication with the surgeon
and interventionist regarding the plan of management and anticipated
complications makes the team better equipped and ready for any eventuality.
Diligent monitoring is required to assay and manage the dynamic situation
during procedure. Continuity of postprocedural neurocritical care is a must
to ensure best outcome.
KEY POINTS
• Neuroanesthesiologist plays a major role in perioperative management
of patients with complex neurovascular lesions and provides continuity
of care in preoperative stabilization, intraprocedural management, and
neurocritical care.
• Management of intracranial aneurysm requires either surgical clipping
or endovascular coiling with management of potential complications like
rebleeding, vasospasm, hydrocephalus, and seizures.
• Management of AVM may require a combination of surgery, embolization,
and radiosurgery.
• Neurovascular lesions like intracranial aneurysms and AVM require
precise dynamic hemodynamic management in communication with the
proceduralist.
• Multidisciplinary management involving neurosurgeon, neurointerventionist,
neuroanesthesiologist, and neurocritical care team with open channels of
communication forms the basis of good outcome.
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High-flow Nasal Oxygenation: A Fad? 277
CHAPTER
19 High-flow Nasal Oxygenation:

A Fad?
Manpreet Singh, Lakesh Kumar Anand
INTRODUCTION
The first line of treatment in hypoxia is oxygen therapy and this remains
the mainstay in today’s anesthetic practice. There are various ways of
oxygen delivery and the common oxygen delivery devices that are available
in market can be classified as low-flow systems (nasal cannula, simple
facemask, partial rebreathing, or non-rebreathing reservoir mask) and
high-flow systems (Venturi mask). Both have advantages and disadvantages.
Low-flow systems are comfortable and simple to use but are unable to
provide consistent oxygen concentrations in various settings. High-flow
systems provide consistent oxygen concentrations in most situations but
are uncomfortable for the patients. The choice of a specific device is based
on the indications for its use, the underlying pathology, patient’s breathing
pattern and tolerance.1
Airway manipulation is usually uneventful but sometimes may result
in adverse events like hypoxia, respiratory, or cardiac arrest. Intensive care
patients often require high concentrations of oxygen to combat their oxygen
demands.2 Patients presenting with acute respiratory failure (ARF) are
tachypneic and have high peak inspiratory flow rate. High respiratory rate
leads to entrainment of room air around the face mask or the nasal cannula
leading to dilution of inspired oxygen concentration. High peak inspiratory
flow may also exceed the oxygen flow delivered by the traditional oxygen
devices.3,4 Moreover, adequate humidification cannot be achieved with low
flow devices. These deficiencies in the existing oxygen delivery devices led to
the development of high-flow nasal oxygen (HFNO) system which is based
on the ability of nasal cannulae to achieve positive airway pressure in the
neonate. HFNO supplies warm, humidified oxygen/air mixtures at flows up
to 60–120 L/min. The inspired oxygen fraction (FiO2) can range from 0.21
to 1.0.
The importance of oxygenation in anesthesia practice was also highlighted
in 4th National Audit Project (NAP4) of the Royal College of Anaesthetists,5
Difficult Airway Society (DAS) guidelines for intubation,6 intubation in
critically ill adults,7 and extubation.8 Since the publication of these guidelines,
HFNO has been used as a technique that can be used in both emergency
and elective anesthesia,7 intensive care, and emergency management of the
airway.9 The DAS intubation drills5 recognized the efficacy of HFNO as a
component for pre-oxygenation and apneic oxygenation. Recent literature
in the intensive care unit (ICU) settings indicates that HFNO achieves better
oxygenation and improves patient comfort as compared to conventional
oxygen therapy.
EQUIPMENT FOR HIGH-FLOW NASAL OXYGENATION

Several devices are now available in the market for administration of HFNO.
Typically, the device consists of special wide bore nasal cannulae or prongs
which are connected to an oxygen flowmeter with an oxygen/air gas mixer
and gas analyzer. Depending on the device used, the HFNO equipment
offers gas flow rates between 60 L/min and 120 L/min. The supply system
requires an intermediate (50–55 psig) pressure gas supply of air and oxygen.
The attached heating system and the humidifier supplies gases between
33°C and 43°C with humidity between 95% and 100%.10
Some studies reflected that HFNO generates continuous positive airway
pressure (CPAP) effect. The HFNO generates pressure inside the pharynx at
flows between 0 L/min and 60 L/min. This increase in pressure to 10 L/min
flow produces around 0.8 cm H2O increase in expiratory pressure. Other
factors associated with increased pressure are closure of mouth (2 cm H2O),
female gender (0.6 cm H2O), and increased height (0.5 cm H2O per every
10 cm).11
PHYSIOLOGICAL BASIS FOR USE OF HIGH-FLOW

NASAL OXYGEN
At rest, a healthy individual breathing through nose can generate gas flows
between 15 L/min and 20 L/min. This dry atmospheric gas is heated and
humidified in the nose because of the increased surface area provided by
nasal turbinates. The gases that are inhaled may reach 36°C temperature
and 80–90% humidification while passing through upper airway. It is to
be observed that the flow rate may reach up to 120 L/min during exercise
or during respiratory distress. This increased flow may lead to increased
fluids loss and higher metabolic oxygen requirement to achieve warm
and humidified gases. These types of flows are feasible only for shorter
periods and are limited by fatigue. Supplying cold and dry gas to patients
with a higher oxygen requirement can exacerbate heat loss. It often causes
discomfort and may lead to lesser compliance with therapy. A decrease in
relative humidity below 50% results in drying of secretions and a reduction
in cilial function leading to a poor mucous flow.12 The physiological effects
and mechanisms of action of HFNO are illustrated in Table 1.
Table 1: Physiological effects and mechanisms of action of HFNO.

Effects Mechanism of action
ashout of pharyngeal
W HFNO generates an oxygen reservoir and rebreathing of
dead space CO2 is minimized. It decreases dead space and increases
alveolar ventilation beyond minute ventilation ratio.13
ecrease in work of
D •• The HFNO warms and humidifies the inspiratory gas.
breathing There is significant reduction in energy requirement
(metabolic work) associated with gas conditioning.13
•• High gas flow reduces upper airway resistance resulting
in decreased respiratory effort.
lveolar recruitment or
A •• HFNO generates positive airway pressure ranging from
CPAP effect (mean 2.7 cm H2O to 7.4 cm H2O).11,14
•• The degree of pressure generated depends on several
factors:
–– Upper airway geometry.
–– Flow rate.
–– Nasal or oral breathing.
–– Size of cannula in relation to size of nostrils.
–– The level of CPAP generated and its effects depend
on the presence and extent of gas loss around the
nasal cannula and whether the mouth is open or
closed.
•• In acutely hypoxemic patients, the level of CPAP deter
mines the increase in end-expiratory lung volume.11
•• In COPD patients, it counterbalances PEEPi that
results in a reduction in spatial respiratory effort.15
Improvement of HFNO provides warmed and humidified air which
mucociliary clearance reduces the viscosity of tracheobronchial secretions
function improves the mucociliary function, reduces dryness of
upper airways, and improves clearance of secretion to
provide comfort for patients.13
Providing accurate The high gas flow decreases variability of ambient air
constant FiO2 entrainment, despite variation of the respiratory pattern. It
minimizes dilution of oxygen with room air and therefore
the delivered FiO2 closely matches set FiO2.4
(CO2: carbon dioxide; COPD: chronic obstructive pulmonary disease; CPAP: continuous
positive airway pressure; FiO2: fraction of inspired oxygen; HFNO: high-flow nasal
oxygen; PEEPi: intrinsic positive end-expiratory pressure)
CURRENT CLINICAL APPLICATIONS

Historically, HFNO was mainly used in neonatology. Its application has
been extended to critical care and anesthesia only recently. HFNO shows
beneficial effects, i.e.:
• It reduces respiratory rate and dyspnea

• Increases comfort and improves oxygenation16
• It is easy to apply and manage
• There is minimal risk of skin irritation and breakdown
• There is less workload for the nurse compared to non-invasive ventilation
(NIV)
• There is increased nasal cannula stability with respect to conventional
high-flow mask
• It causes less claustrophobia
• The patient can mobilize, eat, drink, and communicate during therapy
• Requires less technical skills and training.
In comparison to NIV, HFNO is much easier to implement as it requires
less technical skills and training and also reduces the workload of ICU staff.17
Practical aspects about use of HFNO (Fig. 1) are:
• Apply nasal prongs but these should not completely occlude the nasal
passages
• Start initial flow rate at 30–40 L/min so that patient’s increased demand
can be met
• Set initial temperature at 37°C or less
• Increase FiO2 until satisfactory SpO2 is achieved
• Increase the administered oxygen flow until the respiratory rate decreases
and a stable SpO2 is obtained
• Water reservoir should be placed as high as possible above the humidifier
• Heart rate, respiratory rate, and SpO2 should be continuously monitored
• The gas flow and FiO2 must be adjusted based on the clinical response
which is usually expected within 1 hour
• Reduce FiO2 to 0.05–0.10 and reevaluate after 1–2 hours; reduce the flow
rate by 5 L/min and reevaluate after 1–2 hours
Fig. 1: Components of high-flow nasal oxygen (HFNO).

• While weaning from HFNO consider flow rates <25 L/min and FiO2
< 0.40
• If there is no improvement after 1–2 hours, the escalation of treatment
should be considered.17
Though uncommon, discomforts reported by patients include: irritation
of nasal mucosa, feeling warmth, noise, and dislocation of cannula, and
limited movement. More importantly, there is always the risk of delayed
intubation.2
Guidance for use of NIV cannot be translated directly to the use of HFNO
as there are situations in which HFNO can be used effectively where NIV is
contraindicated. For example, apneic patients and those undergoing shared
airway surgical procedures cannot be oxygenated with NIV. At present,
there are no published guidelines describing contraindications to HFNO
therapy. However, the proposed contraindications to HFNO in critical care
and anesthesia include:18
• Severe nasal obstruction
• Psychiatric patients
• Agitated, noncooperative patient
• Those who have not given consent
• Procedural oxygenation for patients who have a high risk of aspiration
• Maxillofacial trauma
• Basal skull fracture with profuse nasal bleeding
• Recent nasal trauma or surgery.
INDICATIONS OF HIGH-FLOW NASAL

OXYGEN IN CRITICAL CARE
Acute Hypoxemic Respiratory Failure
Emerging evidence in patients with ARF of different etiologies suggests
that HFNO effectively improves oxygenation in most patients. Results from
several studies prove the superiority of HFNO to conventional forms of
oxygen delivery with regard to improving arterial oxygenation, reducing
respiratory rate, dyspnea, and clinical signs of respiratory distress and
increasing patient comfort.
A pilot study was conducted where HFNO was used as rescue therapy
in patients of ARF who had persistent hypoxemia despite 1 hour of
conventional oxygen therapy. In these patients, there was no immediate
indication for tracheal intubation. HFNO was applied for a median time
of 2.8 days (maximum 7 days). It was well tolerated by most patients and
helped to avoid intubation in 70% of them.16
Another study evaluated HFNO in ICU patients admitted for severe ARF
due to influenza A/H1N1. Twenty patients who were unable to maintain
oxygen saturation >92% with conventional oxygen therapy were treated

with HFNO. The therapy was successful in 45% of patients. Eight patients
on vasopressors required intubation within 24 hours. The nonresponders
presented a lower PaO2/FiO2 after 6 hours of HFNO therapy and required
higher oxygen flow rate.19
A multicenter randomized controlled trial (RCT) was conducted in 310
patients from 23 French ICUs, who had hypoxemic ARF (PaO2/FiO2 ratio 300
mm Hg, due to pneumonia). Patients were randomly allocated to receive
standard oxygen through a facemask, HFNO or NIV. The results showed
that the rate of tracheal intubation was decreased among patients treated
with HFNO but these differences were statistically insignificant. There was
a significantly reduced mortality rate in patients who received HFNO, both
during their ICU stay and within 90 days after discharge.20,21
Furthermore, the sequential use of HFNO and NIV was evaluated in a
prospective observational study done in 28 hypoxemic patients. Twenty-
three (82%) of these patients were affected by ARDS. HFNO was applied
for 2 hours followed by NIV for 1 hour totaling to 16 and 8 hours/day,
respectively. Both devices significantly increased PaO2 and decreased
respiratory rate as compared to, standard oxygen therapy but the results
were better with NIV. However, HFNO was better tolerated than NIV and
authors concluded that HFNO can be used as a bridge between NIV sessions
to prevent deterioration of oxygenation.22
However, HFNO, if not properly used, may result in failure of the therapy.
In a retrospective observational study conducted in adult patients, the
authors reported a series of HFNO failures that lead to delayed endotracheal
intubation with adverse effects. All these patients had respiratory failure.
The authors attributed this failure to an increased risk of respiratory muscle
failure and cardiac dysfunction due to prolonged ineffective ventilation.
Early indicators of HFNO failure could be little or no improvement in
oxygenation, persistent tachypnea, and thoracoabdominal asynchrony 30
minutes after the onset of HFNO.23 Other factors associated with its failure
were circulatory shock requiring administration of vasopressors, a sepsis-
related organ failure assessment (SOFA) score ≥ 4, an acute physiology and
chronic health evaluation II (APACHE II) ≥ 12 on admission and a PaO2/
FiO2 ratio < 100 mm Hg after 6 hours of treatment.19,21
Looking at the current evidence, it can be summarized that HFNO
plays a significant role in treatment of hypoxemia due to ARF. It causes
improvement in patients who are less responders to conventional techniques
of oxygen therapy. It shows improvement in oxygenation of patients who do
not respond to conventional forms of oxygen therapy. It has shown that
this improves functional residual capacity (FRC) and reduces respiratory
efforts when provided with inspiratory pressure support. It may be useful
in patients whose hypoxemia is highly dependent on alveolar collapse.
Hypoxemia Induced by Cardiogenic Acute

Pulmonary Edema
By improving oxygenation and at the same time reducing cardiac afterload
through low intrathoracic CPAP generation, HFNO might also be beneficial
in treatment of acute cardiogenic pulmonary edema. In a case series of
five patients with refractory hypoxemia due to acute cardiogenic pulmonary
edema, significant improvement was observed after 24 hours of HFNO
treatment tried after persistent hypoxemia following NIV.24
On the other hand, another RCT compared HFNO with conventional
oxygen therapy in patients who presented to the emergency department
(ED) with cardiogenic pulmonary edema. This study was conducted in 128
adults, 18 years or older. There was no significant difference between the
two groups with regard to rate of admission, length of ED and hospital stay,
use of NIV or intubation, and mortality rate. There was an insignificant
difference in the potential to decrease the severity of dyspnea during the first
hour of treatment.25 Since there is not enough literature where HFNO had
been compared with non-invasive CPAP, it cannot be recommended as the
technique of choice for patients with hypoxia along with acute cardiogenic
pulmonary edema.
Respiratory Failure after Extubation in the

Intensive Care Unit
The period immediately after extubation is very crucial in the ICUs. This is
because there is a transition from mechanical ventilation to spontaneous
breathing. HFNO helps in providing adequate oxygenation and facilitates
the expectoration. This further reduces the respiratory efforts and thus
there is prevention of respiratory failure after extubation. Incidence of
reintubation also decreases drastically.
A multicentric trial at six French ICUs was conducted for 3 years. In this
trial, it was aimed to determine whether HFNO therapy was comparable
to bilevel positive airway pressure (BiPAP) for prevention or resolving of
ARF after cardiothoracic surgery. A total of 830 patients who developed ARF
following cardiothoracic surgery were recruited for the study. They studied
treatment failure and mortality during their ICU stay. It was concluded
that HFNO therapy was not inferior to BiPAP and there was no significant
difference as regards ICU mortality. The findings supported HFNO use in
ICU.26
Another multicenter RCT was conducted in seven Spanish ICUs
to determine if the HFNO is superior to standard oxygen therapy and
whether it can prevent extubation failure or reintubation in patients being
mechanically ventilated. A total of 527 patients were randomly allocated
to receive either HFNO or conventional oxygen therapy for 24 hours after

planned extubation. They observed that the incidence of reintubation rate
was significantly decreased with HFNO and the incidence of postextubation
respiratory failure within 72 hours was also lower in the HFNO group. It was
observed that the time before reintubation was similar in both the HFNO
and control groups.27 The same authors in a subsequent RCT studied 604
patients who were at high risk of failure of extubation. They found that
HFNO was more beneficial as compared to NIV in preventing reintubation
and respiratory failure after extubation.28
Optiflow® to prevent post-extubation hypoxemia after abdominal surgery
(OPERA) trial evaluated the effect of HFNO for prevention of hypoxia in
patients undergoing major abdominal surgery. This trial was a multicentric
RCT conducted at three university hospitals in France. The primary endpoint
was an absolute risk reduction of hypoxemia at 1 hour after extubation
and later when the treatment was discontinuation. Secondary outcomes
included occurrence of pulmonary complications within 7 postoperative
days, duration of hospital stay, and in-hospital mortality. The results from
this trial did not support use of HFNO over conventional oxygen therapy
in patients undergoing major abdominal surgery. Early preventive use of
HFNO therapy after extubation did not improve pulmonary outcomes as
compared with standard oxygen therapy.29
Subsequently, a meta-analysis compared HFNO with conventional
oxygen therapy via face mask in adult patient’s extubated postcardiac
surgery. The HFNO was associated with less “escalation of therapy” (e.g.
the need to increase HFNO flow, crossover to NIV) but the reintubation
rate was similar.30
Considering the advantages of HFNO over standard oxygen therapy,
it may be considered as a standard treatment after extubation of all low-
risk patients in the ICU. It has the potential to facilitate expectoration
and it reduces respiratory work. Some patients who are at a high risk of
reintubation after extubation may benefit from NIV to prevent respiratory
failure.
INDICATIONS AND PROCEDURES IN ANESTHESIA

Preoxygenation and Apneic Oxygenation
during Intubation
Preoxygenation before induction of anesthesia and tracheal intubation is a
very well-accepted technique. It helps to increase body oxygen stores and
thus delays the onset of arterial hemoglobin desaturation during the period
of apnea. Since it is difficult to predict difficult airway and mask ventilation
in all patients, it is desirable to preoxygenate all patients. Preoxygenation
followed by “apneic oxygenation” is the provision of additional oxygenation

in unventilated airways after induction of anesthesia and use of muscle
relaxants to prolong the safe apnea period. It is observed that the rate at
which oxygen is absorbed in the alveoli is greater than accumulation of CO2
in the capillaries. The pressure gradient thus generated allows a mass flow
of gas from a patent pharynx to the alveoli provided the airway is open.
Recently, a physiological study was conducted and authors used three
laboratory airway models to investigate the method of CO2 clearance in
apneic patients using transnasal humidified rapid-insufflation ventilatory
exchange (THRIVE). The findings of study suggested that enhanced CO2
clearance was observed under apneic conditions with THRIVE. This can be
explained as there can be interplay between entrained and highly turbulent
supraglottic flow vortices created by HFNO and cardiogenic oscillations.31
This was checked in comparison to classical apneic oxygenation.31
The THRIVE administered by HFNO might extend the safe apneic
period thus allowing a smooth endotracheal intubation rather than a fast
conducted procedure in patients with anticipated difficult intubation. A
study evaluated THRIVE in 25 patients with anticipated difficult airways
who were being administered general anesthesia (GA) for hypopharyngeal
or laryngotracheal surgery. For preoxygenation, HFNO was administered at
a flow of 70 L/min for 10 minutes with the head elevated to 40°. The head
was lowered to 20° after induction of anesthesia to facilitate laryngoscopy.
HFNO was continued until a definitive airway was established. No patient
experienced arterial desaturation of less than 90% during the period of
apnea averaging 14 minutes.32
Another RCT compared THRIVE with face mask oxygenation in 40
patients undergoing emergency surgery. Arterial blood gases difference
was insignificant between the study group and control. No airway rescue
maneuver was required, and there was no difference in number of
laryngoscopic attempts between the two groups. The mean apnea time was
significantly longer in the THRIVE group as compared to the control group.33
Conceptually, HFNO offered advantages over traditional preoxygenation
and apnea oxygenation techniques.
Contradictory to above studies, a randomized crossover study in healthy
volunteers was conducted to compare the EtO2 following a 3 minutes
preoxygenation with HFNO and face mask. This study did not find HFNO
as a reliable method of preoxygenation before the induction of anesthesia.34
The use of HFNO will be particularly useful in situations where difficult
and prolonged intubation is predicted. However, there is a paucity of data
for the use of HFNO in difficult airway scenarios. Nevertheless, despite the
lack of concrete evidence, HFNO has gained traction and is now advocated
over standard nasal oxygen for oxygenation before intubation of critically
ill patient.7 For preoxygenation, HFNO offers many advantages over
conventional oxygenation in patients with anticipated difficult airways. It

is thus believed that all operating theaters and ICUs should have access to
this technique.
Rapid Sequence Induction/Intubation

Rapid sequence induction (RSI) of anesthesia is most often used during
emergency surgery. Conceptually preoxygenation and apneic HFNO can
provide additional time for airway manipulation during RSI, that can be
utilized in both anticipated and unanticipated difficult airway.
However, there is limited literature specifically examining the use
of HFNO during RSI. For example, a survey explored the practice of RSI
and revealed that only 6% of respondents routinely used apneic oxygen
techniques during laryngoscopy, although no differentiation was made
between standard nasal oxygen and HFNO in this study.35
An RCT of 40 patients, with an average body mass index (BMI) of 26,
compared HFNO with face mask preoxygenation during RSI. The authors
did not demonstrate any significant difference between the two groups in
terms of SpO2, PaO2, and CO2 in arterial blood, or the pH. The intubation
grades were similar between the two groups, but a statistically significant
increase in mean apnea time before intubation was noted in the HFNO
group (248 seconds vs 123 seconds).33 It was suggested that this could
be due to the fact that the blind operator performed a more thoughtful
laryngoscopy. It was not because of prolonged time required to protect the
airway in patients using HFNO.
Awake Fiberoptic Intubation

Awake fiberoptic intubation (FOI) is considered the most reliable skill in
the management of anticipated difficult airways.5 However, the technique
requires expertise and very commonly is associated with arterial desaturation.
Currently, there is no gold standard technique of oxygenation during FOI
even though there is evidence to show that the use of HFNO can improve
oxygenation and prevent desaturation during awake FOI.
In a prospective observational study, HFNO was used during awake FOI
in 50 patients. They faced no difficulty when nasal intubation was done
despite the presence of nasal cannulae placed for HFNO. No desaturation
or hypercapnia was reported in any patient.36
In another prospective observational study done in 600 patients
undergoing awake FOI, HFNO was used in 49% cases at the beginning of the
study but over time it was used in almost 100% cases. Both, the incidence
of complications and desaturation was reduced in HFNO group.37 Despite
lack of statistically significant benefits, the authors reported that HFNO is
the standard oxygenation strategy for awake FOI in their institute and they
recommend the same.7
Extubation and Postoperative Support

Oxygenation before extubation has become a standard practice to prevent
diffusion hypoxia, more so in the high-risk patients. Complications such as
postoperative respiratory failure and hypoxemia in these patients increase
morbidity, mortality, and length of hospital stay further increasing the
financial burden. HFNO is recommended immediately after extubation as
a method to assure oxygenation in preference to conventional facemask
methods. However, published research is limited to the use of HFNO for
extubation in ICU and may not be directly translatable to anesthesia.38
The evidence suggests that HFNO has theoretical advantages and should
not be considered inferior to standard oxygen delivery methods.
Surgical Procedures Sharing/Involving the Airway

In airway sharing surgeries or airway procedures such as laryngotracheal
surgery or fiberoptic bronchoscopy, prolonged apneic oxygenation with
HFNO have shown promising results during GA. A recent study showed that
HFNO provides superior gas exchange compared to traditional oxygenation
techniques while avoiding the risks associated with jet ventilation.39 However,
in the absence of ventilation, the main limitation of apneic oxygenation
with HFNO is that it causes an increase in PaCO2 leading to respiratory
acidosis.9
The THRIVE study demonstrated that preoxygenation with HFNO prolonged
apnea time in patients with difficult airways who received GA. Apneic
oxygenation was used for a prolonged period until the airway was secured.
Apnea times of 5–65 minutes was achieved without oxygen desaturation to
less than 90% and they reported a mean EtCO2 rise of 1.13 mm Hg/min.32
Later many similar studies, achieved comparable apnea times with
HFNO. It was observed that patients with a high BMI can desaturate
rapidly despite high HFNO as compared to patients with a normal BMI.
They recommended careful planning to minimize surgical time in obese
patients and in those with complex stenosis.32,41 They also measured CO2
accumulation with HFNO and noted a mean rise of EtCO2 at the rate of
0.9 mm Hg/min. However, the rate of mean PaCO2 rise in these studies
was disproportionately greater at 1.8 mm Hg/min.32,40 These results should
warn the anesthesiologists that capnography at the end of the procedure
underestimates CO2 accumulation in blood.
It is interesting to note that, contrary to the above studies, a retrospective
observational study examined the use of HFNO maintaining spontaneous
ventilation with intravenous anesthesia. This included 26 adult patients who
required airway surgery for airway compromise or respiratory distress due
to stridor (16 patients), or dyspnea (10 patients). Anesthesia was induced
and maintained with propofol infusion and patients were allowed to breathe
spontaneously. There were no episodes of apnea or complete airway
obstruction during induction of anesthesia. The median level of EtCO2 at
the end of the spontaneous ventilation period was 51 mm Hg. The average
rate of increase in EtCO2 was 23 mm Hg/min which is surprisingly lower
than that reported with apneic techniques.32
Obstetric Anesthesia
The gravid uterus produces a reduction in FRC and the pregnant women
have increased metabolic rate, which predisposes the gravid mother to rapid
desaturation and hypoxemia. Furthermore, difficult intubation is observed
more frequently in the obstetric population with an incidence of failed
intubation rates approximating 1 in 390.42
The Joint Association of Obstetric Anesthesiologists and DAS intubation
guidelines43 recommend preoxygenation in preparation for GA to obtain
an EtO2 of ≥90% and mention the potential use of HFNO. Despite studies
reporting encouraging results in nonpregnant women, more studies
are required in pregnant women before justifying its use. At the time of
publication, HFNO was considered as an option for preoxygenation but not
openly supported because of lack of evidence in the obstetric population.
Pediatric Anesthesia
Pediatric patients are less tolerant to apnea than adults. They experience
rapid desaturation and hypoxemia due to higher basal metabolic rate,
reduced FRC and a higher closing capacity.44 In pediatric ICU, HFNO has
been used for several years in awake, spontaneously breathing children
with respiratory failure. It is also used for ventilator weaning in children.
Generally, the flow rate of 2 L/kg/min is used for neonates and 1 L/kg/
min for infants.45 However, the use of HFNO during anesthesia is less
established.
The higher rate of CO2 accumulation reflects the higher basal metabolic
rate in this age group as compared to adults.32,40 An additional series
successfully demonstrated use of HFNO with 100% oxygen flow in 20 children
aged 5 days–11 years, for a variety of procedures including surgery on the
airway, anticipated difficult airway, flexible bronchoscopy, and comorbid
apnea risk. The SpO2 was maintained between a maximum of 96% and a
minimum of 77%. One patient required rescue oxygenation.46 More studies
are required to observe the effect of HFNO in pediatric patients.
CONCLUSION
Several clinical studies and meta-analysis indicate that HFNO system is
more effective in improving oxygenation than conventional oxygen therapy
in different settings of ICU and anesthesia practice. In the ICU, patients

with mild to moderate acute hypoxemic respiratory failure are most likely
to benefit from this therapy. In patients with predicted or expected difficult
airways, HFNO prevents desaturation and increases safety during elective
intubation. Compared to standard anesthetic techniques, it can limit
hypoxemia during invasive diagnostic procedures of the airway. However,
the potential risks of HFNO are probably underestimated. The usefulness,
indications, and contraindications of HFNO are not yet completely
understood. Before using HFNO, proper technique and understanding of
its use is recommended.
KEY POINTS
• Oxygen delivery is an important part of anesthetic practice. HFNO therapy
has been added in recent years to more traditional means of oxygenation.
• High-flow nasal oxygen provides high flows of up to 120 L/min of heated
and humidified oxygen/air mixture.
• The physiological effects of HFNO include washout of the nasopharyngeal
dead space, decrease in the work of breathing, increase in alveolar
recruitment, maintenance of mucociliary function and an ability to provide
apneic oxygenation.
• High-flow nasal oxygen should be used at the time of intubation in critically
ill patients, for oxygenation during awake fiberoptic intubation as well as
during short surgical procedures involving the airway.
• There is convincing evidence which demonstrates advantages of HFNO
over other alternative techniques in that it can provide apneic oxygenation
during procedures requiring sharing of the airway with the surgeon.
• Further studies are required to identify indications, contraindications, and
the complete utility of HFNO therapy have not yet completely understood.
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intensive care and anaesthesia. Br J Anaesth. 2018;120(1):18-27.
18. Kotwinski D, Paton L, Langford R. The role of high flow nasal oxygen therapy
in anaesthesia. Br J Hosp Med (Lond). 2018;79(11):620-7.
19. Rello J, Perez M, Roca O, et al. CRIPS Investigators. High-flow nasal therapy in
adults with severe acute respiratory infection: a cohort study in patients with
2009 influenza A/H1N1v. J Crit Care. 2012;27:434-9.
20. Frat JP, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in
acute hypoxaemic respiratory failure. N Engl J Med. 2015;372:2185-96.
21. Messika J, Ben Ahmed B, Gaudry S, et al. Use of high-flow nasal cannula
oxygen therapy in subjects with ARDS: a 1-year observational study. Respir
Care. 2015;60:162-9.
22. Frat JP, Brugiere B, Ragot S, et al. Sequential application of oxygen therapy
via high-flow nasal cannula and noninvasive ventilation in acute respiratory
failure: an observational pilot study. Respir Care. 2015;60:170-8.
23. Kang BJ, Koh Y, Lim CM, et al. Failure of high-flow nasal cannula therapy may
delay intubation and increase mortality. Intensive Care Med. 2015;41:623-32.
24. Carratala Perales JM, Llorens P, Brouzet B, et al. High-flow therapy via nasal
cannula in acute heart failure. Rev Esp Cardiol. 2011;64:723-5.
25. Makdee O, Monsomboon A, Surabenjawong U, et al. High-flow nasal cannula
versus conventional oxygen therapy in emergency department patients with
cardiogenic pulmonary edema: a randomized controlled trial. Ann Emerg Med.
2017;70:465-72.
26. Stéphan F, Barrucand B, Petit P, et al. High-flow nasal oxygen vs noninvasive
positive airway pressure in hypoxemic patients after cardiothoracic surgery.
JAMA. 2015;313:2331.
27. Hernandez G, Vaquero C, Gonzalez P, et al. Effect of postextubation high-flow

nasal cannula vs conventional oxygen therapy on reintubation in low-risk
patients: a randomized clinical trial. JAMA. 2016;315:1354-61.
28. Hernandez G, Vaquero C, Colinas L, et al. Effect of postextubation high-flow
nasal cannula vs noninvasive ventilation on reintubation and postextubation
respiratory failure in high-risk patients. JAMA. 2016;316:1565-74.
29. Futier E, Paugam-Burtz C, Godet T, et al. Effect of early postextubation high-
flow nasal cannula vs conventional oxygen therapy on hypoxaemia in patients
after major abdominal surgery: a French multicentre randomised controlled
trial (OPERA). Intensive Care Med. 2016;42:1888-98.
30. Zhu Y, Yin H, Zhang R, et al. High-flow nasal cannula oxygen therapy vs
conventional oxygen therapy in cardiac surgical patients: a meta-analysis.
J Crit Care. 2017;38:123-8.
31. Hermez LA, Spence CJ, Payton MJ, et al. A physiological study to determine the
mechanism of carbon dioxide clearance during apnoea when using transnasal
humidified rapid insufflation ventilatory exchange (THRIVE). Anaesthesia.
2019;74(4):441-9.
32. Patel A, Nouraei SA. Transnasal Humidified Rapid-Insufflation Ventilatory
Exchange (THRIVE): a physiological method of increasing apnoea time in
patients with difficult airways. Anaesthesia. 2015;70:323-9.
33. Mir F, Patel A, Iqbal R, et al. A randomised controlled trial comparing transnasal
humidified rapid insufflation ventilatory exchange (THRIVE) pre-oxygenation
with facemask pre-oxygenation in patients undergoing rapid sequence
induction of anaesthesia. Anaesthesia. 2017;72:439-43.
34. Hanouz JL, Lhermitte D, Gérard JL, et al. Comparison of pre-oxygenation
using spontaneous breathing through face mask and high-flow nasal oxygen: a
randomised controlled crossover study in healthy volunteers. Eur J Anaesthesiol.
2019;36(5):335-41.
35. Sajayan A, Wicker J, Ungureanu N, et al. Current practice of rapid sequence
induction of anaesthesia in the UK: a national survey. Br J Anaesth.
2016;117(Suppl):i69-74.
36. Badiger S, John M, Fearnley RA, et al. Optimizing oxygenation and intubation
conditions during awake fibre-optic intubation using a high-flow nasal oxygen-
delivery system. Br J Anaesth. 2015;115:629-32.
37. El-Boghdadly K, Onwochei DN, Cuddihy J, et al. A prospective cohort study
of awake fibreoptic intubation practice at a tertiary centre. Anaesthesia.
2017;72(6):694-703.
38. Papazian L, Corley A, Hess D, et al. Use of high-flow nasal cannula oxygenation
in ICU adults: a narrative review. Intensive Care Med. 2016;42:1336-49.
39. Pearson KL, McGuire BE. Anaesthesia for laryngo-tracheal surgery, including
tubeless field techniques. BJA Educ. 2017;17(7):242-8.
40. Gustafsson IM, Lodenius Å, Tunelli J, et al. Apnoeic oxygenation in adults under
general anaesthesia using Transnasal Humidified Rapid-Insufflation Ventilatory
Exchange (THRIVE): a physiological study. Br J Anaesth. 2017;118(4):610-7.
41. To K, Harding F, Scott M, et al. The use of Transnasal Humidified Rapid-
Insufflation Ventilatory Exchange in 17 cases of subglottic stenosis. Clin
Otolaryngol. 2017;42(6):1407-10.
42. Kinsella SM, Winton AL, Mushambi MC, et al. Failed tracheal intubation
during obstetric general anaesthesia: a literature review. Int J Obstet Anesth.
2015;24(4):356-74.
43. Mushambi MC, Kinsella SM, Popat M, et al. Obstetric Anaesthetists’ Association
and Difficult Airway Society guidelines for the management of difficult and
failed tracheal intubation in obstetrics. Anaesthesia. 2015;70(11):1286-306.
44. Jagannathan N, Burjek N. Transnasal humidified rapid-insufflation ventilatory
exchange (THRIVE) in children: a step forward in apnoeic oxygenation,
paradigm-shift in ventilation, or both? Br J Anaesth. 2017;118(2):150-2.
45. Milési C, Boubal M, Jacquot A, et al. High-flow nasal cannula: recommendations
for daily practice in pediatrics. Ann Intensive Care. 2014;4(1):29.
46. Humphreys S, Rosen D, Housden T, et al. Nasal high-flow oxygen delivery in
children with abnormal airways. Paediatr Anaesth. 2017b;27(6):616-20.
Double-lumen Endotracheal Tubes 293
CHAPTER
20 Double-lumen Endotracheal
Tubes: From History to Present
and the Future
Lokesh Kashyap, Magesh Parthiban
INTRODUCTION
With the introduction of inhalational anesthesia in the 1840s and subsequent
evolution of general and regional anesthetic techniques, modern and safe
surgery for the majority of the general surgical procedures is possible.
However, it may be difficult to achieve this safety in thoracotomies.1 Major
challenges during thoracic anesthesia are firstly, collapse or isolation of the
lung during open chest surgery due to mediastinal shift and “pendelluft”
and secondly, spillage of contaminants from the affected lung to the healthy
lung.2 A solution to prevent the collapse of the lung was suggested by von
Mikulicz and Sauerbruch where the body of the patient was placed in a
chamber under negative pressure and the head of the patient placed outside
the chamber. At around the same time, Brauer was also able to demonstrate
spontaneous breathing in a patient with open chest while only the head was
put in a positive pressure chamber [similar to continuous positive airway
pressure (CPAP)]. These approaches were later modified further to provide
positive pressure ventilation by intratracheal insufflation. Howard Lilienthal
performed the first successful thoracotomy in 1910 at Mount Sinai Hospital,
New York. An intratracheal insufflation using an air-ether anesthetic was
demonstrated by Elsberg for the surgery.3 However, all these approaches
though useful during surgery, failed to prevent soiling of the normal lung.
Three years after the invention of the endotracheal tube by Guedel
and coworkers, selective ventilation of one-lung was first suggested by
Gale and his colleagues.4 The trachea of the patient was intubated with a
cuffed endotracheal tube and isolation of the operated lung was achieved
by advancing the tube beyond the carina into the normal lung. This also
prevented contamination of the healthy lung.4
Later in 1935, Archibald described bronchial blockers for one-lung
ventilation. They used radiographs and placed a catheter with a balloon into
the bronchus. The trachea was intubated with an endotracheal tube passed
alongside the blocker catheter for ventilation of the normal lung. Later,
another blocker was designed by Magill that could be placed under direct
vision using an endoscope.5 The main disadvantages of bronchial blockers
were a steep learning curve for successful placement and nonavailability of

muscle relaxants at that time. Sudden and violent movements of the patient
during placement were common and often resulted in displacement of the
bronchial blockers. An endobronchial tube with one lumen and double
cuff was designed by Rovenstine in 1936 that could be advanced beyond
the carina and into the bronchus of the healthy lung. Both lungs could be
ventilated on inflation of the proximal balloon, but only the healthy lung
would be ventilated when both cuffs are inflated.6 Subsequently many
endotracheal tubes combined with bronchial blockers and endobronchial
tubes were introduced into anesthetic practice. A ribbon gauze tampon
was used by Crafoord as a bronchial blocker to prevent contamination of
the normal lung.2 Univent tube, a tube with a blocker was introduced in
the 1980s. It has a thin, balloon-tipped blocker placed anteriorly inside
an endotracheal tube. This tube is placed using a fiberoptic broncho-
scope and the blocker is advanced into either bronchus for isolation of the
diseased lung. The endotracheal tube can be used for ventilation in the
postoperative period after withdrawing the bronchial blocker catheter
(Figs. 1A and B).7
Until recently, catheters such as Fogarty embolectomy catheters had
been used for bronchial blockade. Now bronchial blockers have been
designed specifically for use in thoracic anesthesia.8 Arndt blocker can be
placed using a pediatric bronchoscope by coupling its wire-loop snare to the
tip of the bronchoscope.9 The risk of airway trauma is less as these balloons
have low-pressure. A distinct disadvantage of the bronchial blockers is that
suction and bronchoscopic examination is not possible. Also, it is very
difficult to re-expand the collapsed operated lung during surgery. An ideal
isolation of the healthy lung cannot be achieved, which may result in cross-
contamination when the blocker balloon is deflated. All these demerits were
overcome with the use of double-lumen tubes (DLTs). With these advances
in thoracic anesthesia, the thoracic surgeon could do these operations that
were previously considered impossible.
A B
Figs. 1A and B: (A) Univent tube; (B) Bronchial blocker.
HISTORY OF DOUBLE-LUMEN TUBES

The lung isolation techniques in early days were conducted at the University
of Bonn, Germany by physiologists Eduard Pflüger and Claude Bernard
during their experiments on gaseous exchange across the blood into the
lungs. They designed a catheter for sampling gas from different areas of lung
in dogs. Wolffberg later used this catheter and introduced an endobronchial
tube.10 Later Loewy and von Schrotter, conducted experiments on human
volunteers using this airway device to test the Fick principle for measurement
of cardiac output.11
Subsequent research on respiratory physiology and independent lung
spirometry by Head, Wolffberg and Werigo propelled the advancement
in lung separation techniques. Head designed the first DLT in 1889 by
combining a short tracheal tube with a longer one. Following his work,
Werigo used a coaxial DLT in dogs through a tracheal stoma. Walter Hess
was the first to introduce a hook to prevent the endotracheal tube from
advancing too far beyond the carina. These experiments by physiologists
resulted in better understanding of respiratory physiology and subsequent
advancement in thoracic anesthesia.12
It was not until 1949, Carlens, a physiologist from Sweden, described the
use of DLT for intubation of the left lung for differential bronchospirometry.
This provided just the right impetus for further advancement in airway for
lung isolation. He designed a DLT by joining together two cuffed tubes.
When the cuff located in the trachea is inflated, both the lungs can be
ventilated. The left lung can be isolated by inflating the distal bronchial
cuff and ventilation can be directed by clamping of either the tracheal or
bronchial lumen. He also designed a carinal hook. This hook, although
helpful for placement in the bronchus carried the risk of serious damage
to the airway (Fig. 2).13 Bjork and coworkers used the Carlens tube for the
Fig. 2: Carlens tube with carinal hook.

first time during thoracic surgery in 1950.14 Following the widespread use
of Carlens tube, innumerable reports of serious airway damage due to the
carinal hook were reported. This prompted Bryce-Smith in 1959 to develop
a left-sided DLT without a carinal hook.15
After the popularity of left-sided DLTs for thoracic surgery, there was
a need for a right-sided DLT. The main problem in intubation of the right
main bronchus was the occlusion of the right upper lobe bronchus. The use
of a right-sided DLT resulted in DLT malposition and accidental clamping
of bronchial segment during surgery. In 1936, the first attempt for a right-
sided DLT was made by London-based thoracic surgeon and anesthetist
Wally Gordon and Ronald Green. Together they designed “Gordon-Green
tube” which had a carinal hook and a cuff with a slot at the distal end.
This ensured adequate ventilation of the right upper lobe. However, even a
slight displacement of this tube resulted in difficulty in ventilation (Figs. 3A
and B).16 In 1960, Malcolm White described a version of the Carlens DLT for
right lung which had a slot in the bronchial cuff.17 In the same year, Bryce-
Smith and Salt introduced a right-sided DLT without the carinal hook by
modifying the Gordon-Green tube.18
Double-lumen endotracheal tubes had several advantages during one-
lung ventilation. It not only allows the diseased lung to collapse but the
operated lung can also be safely reinflated during the procedure, thus
providing the surgeon with a good motionless surgical field. It protects the
healthy lung from contamination. A distinct advantage of DLT is the ability
to remove contaminants from the operated lung by suction before the lung
is re-expanded. However, the DLT was not popular during early period due
to difficulty in proper placement in the bronchus.
Robertshaw tube, introduced in 1962 by Frank Robertshaw, was the most
significant advancement in thoracic anesthesia. It solved the disadvantages
of the previous DLTs and established itself as the gold standard. Firstly,
the risk of serious airway damage was less due to the absence of a carinal
hook. Secondly, the rubber Robertshaw tube was designed with wider
A B
Figs. 3A and B: (A) Gordon-Green double-lumen tube; (B) Tube for the right upper
lobe bronchus has a slot.
Fig. 4: Left-sided Robertshaw double-lumen tube.
lumen incorporating pilot tubes for cuff inflation, and the two semicircular
“D-shaped” tubes placed side-by-side instead of the conventional front-back
orientation. These modifications reduced kinking, improved gas flow during
one-lung ventilation and improved suction through the lumen (Fig. 4). Since
the early 1980s, disposable DLTs have replaced the red rubber tubes which
had thick walls and a smaller lumen. Hence, they offer less resistance to
airflow during ventilation. A bigger lumen of disposable DLTs allows easy
passage of the suction catheter and fiberoptic bronchoscope. In comparison
to red rubber tubes, tracheal intubation and bronchial placement are also
easier with disposable DLTs. Moreover, as these tubes are transparent and
any blood and secretions are easily visible. Finally, the cuffs of all disposable
DLT have high-volume and low-pressure which decreases the risk of airway
trauma. The left-sided Robertshaw DLT was designed with an angle of 40° at
the endobronchial portion while the right-sided DLT had an angle of 20°.19
MODERN DOUBLE-LUMEN TUBES

All DLTs used currently for isolation of the lung are based on the design by
Robertshaw and are made of polyvinylchloride. The different DLTs differ in
their design primarily on the modification of the right-sided DLT (Fig. 5).
Currently, the four main manufacturers are MallinckrodtTM (St. Louis, MO),
PortexTM (Keene, NH), SheridanTM (Argyle, NY), and RüschTM.
MallinckrodtTM (Broncho-Cath) Double-lumen

Tubes (Covidien)
It was the first successful disposable tube manufactured by Covidien and was
based on the Robertshaw design. The tracheal cuff is made of polyurethane
which has higher puncture strengths than conventional materials. The
bronchial cuff is blue in color which helps in verifying correct placement
using a fiberoptic bronchoscope. The tip of the endobronchial segment
has a bevel and is slightly curved for easier placement. The area from the
Fig. 5: Modifications in the bronchial cuff of the right-sided double-lumen tubes

(DLTs) by various manufacturers; (left to right) MallinckrodtTM, PortexTM, RüschTM, and
SheridanTM.
Fig. 6: RüschTM (Teleflex) left-sided double-lumen tubes (DLTs) (37F) (top); MallinkcrodtTM
(broncho-cath) DLT (Covidien) left-sided (37F) (bottom).
distal tip to the tracheal opening is marked with X-ray opaque marker which
aids radiological verification. The S-shaped bronchial cuff of the right DLT
increases the margin of safety during positioning in the right upper lobe
(Fig. 6).20,21
RüschTM (Teleflex)
The RüschTM DLT differs from the MallinckrodtTM tube in that the tip does not
have a bevel. The distal cuff of the right-sided RüschTM DLT has a ventilation
slot for the right upper lobe bronchus. Both the tracheal and the bronchial
cuff of RüschTM DLT are cylindrical in shape (Fig. 6).
A B
Figs. 7A and B: (A) PortexTM (Smith medicals) right-sided double-lumen tubes (DLTs)
(39F); (B) Modification of the bronchial cuff of the right-sided DLT.
PortexTM (Smith Medicals)

The PortexTM DLT is similar to the RüschTM DLT in all aspects except that
the cuff is spherical in shape. The right-sided DLT has a slot similar to the
RüschTM DLT but the cuff is spherical in shape (Figs. 7A and B).
SheridanTM (Teleflex)
The left-sided Sher-I-BronchTM DLT differs from the MallinckrodtTM DLT in
that it has an endobronchial angle of 34°, a longer endobronchial segment
with a beveled endobronchial tip. The bronchial segment of right-sided DLT
has a ventilation slot of 13–14 mm interposed between the two bronchial
cuffs.22
SilbronchoTM
It is made up entirely of silicone and is free of latex. The tip of this tube has a
45° angle. It has a D-shaped wire-reinforced lumen to prevent obstruction or
kinking of the lumen while maintaining the flexibility. It is useful in difficult
situations when the left bronchus is angled at 90° from the trachea when
proper positioning with other disposable DLT is almost impossible.23
Double-lumen Tube for Children

Marraro DLT is currently the only DLT designed for lung isolation in children
younger than 3 years of age. Two uncuffed tubes are joined: shorter one is
the tracheal tube and the longer one is the bronchial tube.24
Double-lumen Tubes in Tracheostomized Patients

Tracheostomized patients present a special situation for lung isolation
as the long conventional DLTs cannot be used. Bronchial blockers are
commonly used in such situations. The first DLT designed specifically for
such patients was introduced in 1991 by Brodsky and coworkers but is not
currently in use.25 The other DLTs commercially available for such patients
are manufactured by RüschTM (Teleflex, USA) and NarukeTM Koken Medical
(Shinjuku-ku, Tokyo, and Japan).
• RüschTM (Teleflex): RüschTM DLT is shorter and curved in comparison
to conventional DLTs. It has an adjustable flange and an adjustable
neckband for stabilization of the tube after its insertion through a standard
tracheostomy stoma. This DLT protects the cricoid by preserving the first
two tracheal rings. The tracheal opening should always be pointed to
the dorsal wall of the trachea during placement. After bronchoscopic
confirmation of a proper placement, this tracheostomy DLT is secured
by a neckband. This is commercially available in three sizes: (1) 75 mm,
(2) 85 mm, and (3) 95 mm. This tube is currently available only in Europe
and Japan.26
• Naruke tubeTM (Koken Medicals): This new endobronchial tube made
up of silicone, spiral, and wire-reinforced DLT similar to SilbronchoTM
DLT was manufactured by Koken Medical (Shinjuku-ku, Tokyo, and
Japan). The tube is constructed in three individual parts—(1) the distal
section beyond the tracheal orifice, (2) the middle section between the
tracheal cuff and the point of bifurcation, and (3) the proximal bifurcated
part—and assembled later. The middle section of the tube called the
“trunk” and is constructed of two thin-walled silicone tubes with an
inner diameter of 5.0 mm that are glued together, are reinforced with
a stainless spiral wire, and covered in a silicone coating. Two pilot
balloons run within the walls of the two inner tubes, one of which
supplies the tracheal cuff. The distal section, containing the bronchial
lumen and the cuff is also wire-reinforced. The dimensions are based
on the MallinckrodtTM DLT. The bronchial cuff is placed 1.2 cm from the
tip while the tracheal orifice is 4.9 cm from the tip. The proximal part
made of two cone-shaped tubes connects the double-lumen airway to
the anesthetic circuit. The diameters of the two inner lumens are larger
than 5.0 mm. The most proximal lumen has an inner diameter of 9.0
mm.27
SELECTION OF APPROPRIATE SIZE

The smallest DLT available is 26F in size and the largest is 41F. DLTs by
MallinckrodtTM, Broncho-cathTM, Sher-I-BronchTM, and RüschTM are of similar
sizes.28 Conventionally, the size of DLT to be used is based on height of the
patient:
Male Female
<160 cm = 37F <152 cm = 32F
<170 cm = 39F <160 cm = 35F
>170 cm = 41F >160 cm = 37F
Selection of appropriate size DLT can also be done using radiographic

imaging by chest X-ray posteroanterior (PA) view and computed tomography
(CT) thorax.
Tracheal width or diameter is calculated in the chest radiograph at the
level of the clavicle at a scale 1:1.
Predicted left main stem bronchus width (LBW) = 0.45 × tracheal
width + 3.3 mm.
Predicted left main stem bronchus diameter (LBD) = 0.68 × tracheal diameter.
Based on the tracheal width and predicted LBW, the appropriate size of
DLT is chosen.29,30
Depth of insertion of a DLT is determined by the following equation:
12 + height in cm/10, for both males and females.
For example, a patient with a height of 160 cm will have a depth of
insertion of DLT of 28 cm at the teeth.31
Another method to calculate the depth of DLT insertion is based on a
correlation between the height (ht) and distance of the tracheal segment
between clavicle-to-carinal (Cl-to-Car) is calculated by the following
equation:32
Depth of insertion (cm) = 0.75 × Cl-to-Car (cm) 10 + 0.112 × height
(cm) + 6.
METHOD OF INSERTION AND CONFIRMATION OF

PROPER PLACEMENT
There are two main techniques of inserting a DLT:
1. Blind approach: DLT is passed via direct laryngoscopy with the stylet in
situ and the endobronchial tip facing anteriorly. After the endobronchial
cuff passes beyond the vocal cords, DLT is rotated to the right or left side
by 90° and the head and neck may be rotated to the opposite side. The
DLT is then advanced to an appropriate depth.
2. Fiberoptic bronchoscope guided: In this technique, the DLT is passed
through the glottis as in blind approach. After passing the glottis,
the stylet is removed and further insertion is guided with the help of
a fiberoptic bronchoscope. Alternatively, a fiberoptic scope may be
inserted in the bronchial lumen of DLT and placement done into the
respective bronchus.
Auscultation can be used to check the placement of DLT but should be
confirmed with fiberoptic bronchoscope.33
CONFIRMATION OF PROPER PLACEMENT

Auscultation for Left-sided Double-lumen Tube
• After insertion of DLT, the tracheal cuff is inflated and auscultation
for confirmation of bilateral air entry is done. Unilateral air entry on
chest auscultation implies that the tracheal opening is too deep in the
bronchus.
• After this the distal cuff is inflated with air, the tracheal lumen is clamped.
This results in the absence of breath sound on the right hemithorax and
presence of air entry on the left side. Air entry in the right hemithorax
indicates that the bronchial cuff is still in the trachea. Presence of right-
sided air entry and absence of left-sided air entry indicates DLT has gone
into the right bronchus.
• After completion of this maneuver, both the lungs are ventilated after
declamping the tracheal lumen. Following which the endobronchial
lumen is clamped. This should result in absent breath sounds on the left
hemithorax and presence of air entry on the right side. For right-sided
DLT, the inverse of these findings is observed in each step.
Fiberoptic Bronchoscopy
To confirm the placement of left-sided DLT (Figs. 8A and B):
• Fiberoptic bronchoscopy is introduced through the tracheal lumen to
confirm the placement of DLT in the left bronchus. Through the tracheal
view, the blue endobronchial cuff should be seen a few millimeters
below the tracheal carina in the left bronchus.
• Identify the take-off of the right upper lobe bronchus which is the only
bronchus with three orifices (apical, anterior, and posterior).
• The next step to insert the fiberoptic bronchoscope into the endobronchial
lumen to confirm its placement. The orifices of both the left upper and
lower lobes must be seen. Avoid occlusion of the left upper lobe.
A B
Figs. 8A and B: (A) Bronchoscopic view of proper double-lumen tubes (DLTs)
placement via tracheal lumen to visualize the carina and the bronchial cuff; and
(B) Correct placement when left bronchial cuff, originally blue in color just disappears
in the left main stem bronchus (right).
Ultrasonography
Recently, lung ultrasound is being used for confirmation of lung isolation.
The interface between the soft tissues of the chest wall and ventilated lung
appears as a hyperechoic line, “the pleural line” on lung ultrasound through
the intercostal approach. In the ventilated lung, there is movement of the
pleura which corresponds to the tidal movement of the lung (lung sliding
sign). In the collapsed lung, lung sliding is absent and the pleural line moves
with each heartbeat in a pulsatile manner (lung-pulse sign). Lung-pulse has
a sensitivity of 93% and specificity of 100% for identification of lung collapse.
Thus, on ultrasonography (USG) if lung sliding is present on one side of
chest and lung-pulse on other, an adequate “functional lung isolation” can
be predicted.34-36
RECENT ADVANCES IN DOUBLE-LUMEN TUBE

• The ClinyTM (Create Medic Co., Ltd, Yokohama, Japan) is a newly
designed right-sided DLT which has a long oblique bronchial cuff and
two ventilation slots for the right upper lobe. The proximal portion of
the bronchial cuff is located immediately opposite the tracheal orifice.
This device is very useful in patients with a very short right mainstem
bronchus.37
• The Papworth BiVent tube is a recently designed DLT for isolation of
lung using a bronchial blocker. It has two D-shaped lumens arranged
in a side-by-side configuration, separated by a central position. The
tube has a preformed posterior concavity and a single inflatable, low-
volume, high-pressure tracheal cuff. At the distal end, there are two
pliable crescent-shaped flanges arising from the central position to form
a forked tip. The purpose of the forked tip is to sit at the tracheal carina.
A bronchial blocker can be advanced blindly through either lumen and
is guided into a bronchus.38
• VivaSight-DL (E.T. view Medical Ltd.) is a left-sided DLT (sizes 37F, 39F,
and 41F only) with a high-resolution camera at the tip of the tracheal
lumen that remains connected to a monitor and allows continuous
visualization of the tracheal carina. It is a recent development in facilitating
and confirming the position of DLT and also to identify its displacement
intraoperatively. Any displacement from the desired position is easily
detected and rapid repositioning is achieved without disrupting the
ventilation. This reduces the need of fiberoptic bronchoscope (FOB),
offers continuous visualization of the position of the DLT around the
carina and is also expected to save time in inserting, confirming, and
repositioning of displaced DLT, once the learning curve is crossed
(Fig. 9).39
Fig. 9: Viva-sight double-lumen tubes (DLTs). Left-sided with camera source at the tip
of the tracheal lumen.
(HDR: high dynamic range)
High-frequency jet ventilation (HFJV) has been successfully used as

an alternative method for lung isolation in thoracic surgeries in pediatric
population.40 HFJV has also been used in mini-thoracotomies in adults
for lung isolation. In future, there may be a trend for use of HFJV in the
operated lung to decrease the incidence of intraoperative hypoxemia and
improve postoperative outcomes.
CONCLUSION
Double-lumen tube has developed from its inception in animal and human
research on physiology into an established anesthetic practice for thoracic
surgical operations. These double-lumen endotracheal tubes and other
lung isolation devices available in various shapes and sizes have been
designed for use in patients ranging from newborns to elderly, patients
with tracheostomy and in difficult airways. These developments would not
have been possible without the revolutionary brilliance and dedication
of physicians. Advances in medical technology, airway equipment and
monitoring over the centuries have contributed significantly to the safety
and better anesthetic management of complex thoracic surgical procedures.
KEY POINTS
• Prevention of collapse of the lung open to the atmosphere and prevention
of spillage from the diseased lung are the greatest challenges in thoracic
anesthesia.
• Initially, this was achieved with the use of bronchial blockers and endo
bronchial tubes but they had their own limitations. These were overcome
by the introduction of DLTs, first designed by Carlens in 1949.
• Robertshaw tube, introduced in 1962, was designed to overcome the
disadvantages of the previous DLTs and established itself as the gold
standard.
• All DLTs in practice today are based on the design by Robertshaw and
are made of polyvinyl chloride.
• Recent advances in the design of DLT with a camera placed near the
tip of the tracheal lumen have resulted in early and easier detection of
malposition of DLT intraoperatively.
• Double-lumen tube has over the years developed from its inception
in research on physiology into an established anesthetic practice for
thoracotomies.
REFERENCES
1. Dumas A. The history of anaesthesia. J Natl Med Assoc. 1932;24:6-9.
2. Brodsky JB, Lemmens HJ. The history of anesthesia for thoracic surgery.
Minerva Anestesiol. 2007;73(10):513-24.
3. Lilienthal H. IV. The First Case of Thoracotomy in a Human Being under
Anaesthesia by Intratracheal Insufflation. Ann Surg. 1910;52(1):30-3.
4. Purohit A, Bhargava S, Mangal V, et al. Lung isolation, one-lung ventilation and
hypoxaemia during lung isolation. Indian J Anaesth. 2015;59:606-17.
5. Magill IW. Anaesthesia in Thoracic Surgery, with Special Reference to
Lobectomy: (Section of Anaesthetics). Proc R Soc Med. 1936;29(6):643-53.
6. Zhao ZR, Lau RWH, Ng CSH. Anaesthesiology for uniportal VATS: double
lumen, single lumen and tubeless. J Vis Surg. 2017;3:108.
7. Inoue H, Shohtsu A, Ogawa J, et al. New device for one-lung anesthesia:
endotracheal tube with movable blocker. J Thorac Cardiovasc Surg. 1982;83:
940-1.
8. Ginsberg RJ. New technique for one-lung anesthesia using an endobronchial
blocker. J Thorac Cardiovasc Surg. 1981;82:542-6.
9. Arndt GA, Buchika S, Kranner PW, et al. Wire-guided endobronchial blockade
in a patient with a limited mouth opening. Can J Anaesth J Can Anesth.
1999;46:87-9.
10. McGrath B, Tennuci C, Lee G. The history of one-lung anesthesia and the
double-lumen tube. J Anesth Hist. 2017;3:76-86.
11. Laszlo G. Respiratory measurements of cardiac output: from elegant idea to
useful test. J Appl Physiol (1985). 2004;96(2):428-37.
12. Head H. On the regulation of respiration. J Physiol. 1889;10:279-90.
13. Carlens E. A new flexible double-lumen catheter for bronchospirometry.
J Thorac Surg. 1949;18:742-6.
14. Bjork VO, Carlens E. The prevention of spread during pulmonary resection by
the use of a double-lumen catheter. J Thorac Surg. 1950;20:151-7.
15. Bryce-Smith R. A double-lumen endobronchial tube. Br J Anaesth. 1959;31:
274-5.
16. Gordon W, Green R. Right lung anaesthesia; anaesthesia for left lung surgery
using a new right endobronchial tube. Anaesthesia. 1957;12(1):86-93.
17. White GM. A new double lumen tube. Br J Anaesth. 1960;32:232-4.
18. Bryce-Smith R, Salt R. A right-sided double lumen tube. Br J Anaesth.

1960;32:230-1.
19. Robertshaw FL. Low resistance double-lumen endobronchial tubes. Br J
Anaesth. 1962;34:576-9.
20. Ehrenfeld JM, Walsh JL, Sandberg WS. Right- and left-sided Mallinckrodt
double-lumen tubes have identical clinical performance. Anesth Analg.
2008;106(6):1847-52.
21. Fischler M. A call to Mallinckrodt for a modified right-sided Broncho-Cath
double lumen tube. Can J Anesth. 2007;54(12):1029-30; author reply 1030.
22. Slinger PD, Chripko D. A clinical comparison of bronchial cuff pressures in
three different designs of left double-lumen tubes. Anesth Analg. 1993;77:305-8.
23. Jeon J, Lee K, Ahn G, et al. Comparison of postoperative sore throat and
hoarseness between two types of double-lumen endobronchial tubes: a
randomized controlled trial. J Cardiothorac Vasc Anesth. 2015;29:121-5.
24. Pawar DK, Marraro GA. One lung ventilation in infants and children: experience
with Marraro double lumen tube. Paediatr Anaesth. 2005;15:204-8.
25. Brodsky JB, Tobler HG, Mark JB. A double-lumen endobronchial tube for
tracheostomies. Anesthesiology. 1991;74:387-8.
26. Masamune T, Matsukawa T, Ookawa I, et al. [Double-lumen tracheostomy
tube (Tracheopart) used in two patients for one-lung ventilation under general
anesthesia]. Masui. 2004;53(12):1418-20.
27. Saito T, Naruke T, Carney E, et al. New double intrabronchial tube (Naruke
tube) for tracheostomized patients. Anesthesiology. 1998;89:1038-9.
28. Brodsky JB, Macario A, Mark JB. Tracheal diameter predicts double-lumen
tube size: a method for selecting left double-lumen tubes. Anesth Analg.
1996;82:861-4.
29. Jesseph JE, Merendino KA. The dimensional interrelationships of the major
components of the human tracheobronchial tree. Surg Gynecol Obstet.
1957;105:210-4.
30. Hannallah M, Benumof JL, Silverman PM, et al. Evaluation of an approach to
choosing a left double-lumen tube size based on chest computed tomographic
scan measurement of left mainstem bronchial diameter. J Cardiothorac Vasc
Anesth. 1997;11:168-71.
31. Brodsky JB, Benumof JL, Ehrenwerth J, et al. Depth of placement of left double-
lumen endobronchial tubes. Anesth Analg. 1991;73:570-2.
32. Chow MY, Goh MH, Ti LK. Predicting the depth of insertion of left-sided
double-lumen endobronchial tubes. J Cardiothorac Vasc Anesth. 2002;16:456-8.
33. Campos JH. Update on tracheobronchial anatomy and flexible fiberoptic
bronchoscopy in thoracic anesthesia. Curr Opin Anaesthesiol. 2009;22:4-10.
34. Ovassapian A. Fibreoptic bronchoscope and double-lumen tracheal tubes.
Anaesthesia. 1983;38:1104.
35. Slinger PD. Fiberoptic bronchoscopic positioning of double-lumen tubes.
J Cardiothorac Anesth. 1989;3:486-96.
36. Klein U, Karzai W, Bloos F, et al. Role of fiberoptic bronchoscopy in conjunction
with the use of double-lumen tubes for thoracic anesthesia: a prospective
study. Anesthesiology. 1998;88:346-50.
37. Hagihira S, Takashina M, Mashimo T. Application of a newly designed right-

sided, double-lumen endobronchial tube in patients with a very short right
mainstem bronchus. Anesthesiology. 2008;109:565-8.
38. Ghosh S, Falter F, Goldsmith K, et al. The Papworth BiVent tube: a new device
for lung isolation. Anaesthesia. 2008;63(9):996-1000.
39. Heir JS, Purugganan R, Jackson TA, et al. A retrospective evaluation of the
use of video-capable double-lumen endotracheal tubes in thoracic surgery.
J Cardiothorac Vasc Anesth. 2014;28:870-2.
40. Hammer GB, Fitzmaurice BG, Brodsky JB. Methods for single-lung ventilation
in pediatric patients. Anesth Analg. 1999;89:1426-9.
CHAPTER
21 High-altitude Pulmonary
Edema
Rashmi Datta, RM Sharma
INTRODUCTION
Altitudes >1,500 m above mean sea level (MSL) affect the health of human
beings adversely. The adverse environmental conditions at such altitudes
areas include a drop, not only in the barometric pressure but also in
temperature and ambient humidity. This affects the oxygen cascade at
all levels up to the Pasteur’s point, i.e. the mitochondria with resultant
hypobaric hypoxia. These hostile environmental conditions at high altitude
(HA) initiate a series of physiological responses to help adapt to the low
pressure of oxygen seen at these altitudes. In some susceptible persons,
these responses may be abnormal or excessive leading to a spectrum of
clinical manifestations, collectively known as acute high-altitude illness
(AHAI). In 1991, the International Society for Mountain Medicine held an
International Hypoxia Symposium which defined and quantified the various
altitudes at which symptoms develop as well as criteria for the diagnosis of
illnesses. These are now known as Lake Louise criteria (Table 1).1,2
On ascending to HA, unacclimatized individuals are at risk of developing
one of three forms of AHAI with an onset ranging from several hours to 5
days:3-5
1. Acute mountain sickness (AMS): A syndrome of nonspecific symptoms
such as dizziness, lassitude, headache, nausea, vomiting, and fatigue
that develops within 6–12 hours of ascent.
2. High-altitude cerebral edema (HACE): Characterized by altered
consciousness, ataxia, and characteristic cerebral imaging.
3. High-altitude pulmonary edema (HAPE): Which is an example of
noncardiogenic pulmonary edema resulting from excessive hypoxic
pulmonary vasoconstriction (HPV). The diagnostic and clinical criteria
are given in Table 2.
Diagnosis of AMS was further modified in 2018 with a scoring system
(Table 3). AMS, HACE, and HAPE are considered to be continuum of
spectrum and the latter two can be fatal if not recognized and treated
promptly. This is different from high-altitude pulmonary hypertension and
chronic mountain sickness (Monge disease) seen in permanent residents
of HA.6
High-altitude Pulmonary Edema 309
Table 1: Lake Louise criteria for the classification of high altitude.

High altitude •• Onset of physiologic effects Because of the large
(1,500–3,500 m) of diminished PiO2 includes number of people who
decreased exercise performance ascend rapidly to 2,500–
and increased ventilation with 3,500 m, high-altitude
lowering of arterial PaCO2. illness is common in this
•• Minor impairment exists in range.
arterial oxygen transport, i.e.
SpO2 is at least 90%, but PaO2 is
significantly diminished.
Very high altitude •• Maximum SpO2 falls <90% as Severe altitude illness
(3,500–5,500 m) the PaO2 falls <60 mm Hg. commonly occurs in this
•• Extreme hypoxemia may occur range.
during exercise, during sleep and
in the presence of high-altitude
pulmonary edema (HAPE) or
other acute lung conditions.
Extreme altitude •• Marked hypoxemia, hypocapnia, This is why no human
(above 5,500 m) and alkalosis are characteristic. habitation occurs above
•• Progressive impairment of 5,500 m.
physiologic function eventually
outstrips acclimatization.
(PaCO2: arterial pressure of carbon dioxide; PaO2: arterial pressure of oxygen; PiO2:
inspiratory oxygen pressure; SpO2: oxygen saturation of arterial blood)
Table 2: 1991 Lake Louise criteria for clinical diagnosis of High-Altitude Pulmonary
Edema (HAPE).
Symptoms Clinical signs
Dyspnea at rest Crepitations or wheeze on auscultation
Cough Central cyanosis
Decreased exercise tolerance Tachypnea
Chest tightness Tachycardia
The diagnosis of HAPE requires at least two symptoms and two clinical signs from
above
HISTORY
Chinese documents from the era of 32 BC describe a report by Tseen
Hanshoo of “air hunger” and hemoptysis seen in a traveler in HA. Others
had described the “Great and Little Headache” mountains on the journey
along the Silk Road. A description of travels in 403 AD mentions monks
developing froth from the mouth when crossing an HA mountain pass.7
Descriptions from Moghul literature in the 1500s described “damgiri,” a
Tibetan name apparently used for AHAI illness.8
Table 3: 2018 Lake Louise Acute Mountain Sickness Score.

0 1 2 3
Headache None at all A mild Moderate Severe headache,
headache headache incapacitating
Gastrointestinal Good Poor appetite Moderate Severe nausea
symptoms appetite or nausea nausea or and vomiting,
vomiting incapacitating
Fatigue and/or Not tired or Mild fatigue/ Moderate Severe fatigue/
weakness weak weakness fatigue/ weakness,
weakness incapacitating
Dizziness/light- No dizziness/ Mild dizziness/ Moderate Severe dizziness/
headedness light- light- dizziness/ light-headedness,
headedness headedness light- incapacitating
headedness
(Mild AMS: 3–5 points; moderate AMS: 6–9 points; severe AMS: 10–12 points)
For a positive acute mountain sickness (AMS) definition, it is mandatory to have a
headache score of at least one point, with a total score of >3.
Although symptoms can develop within 6 hours of gain in altitude, it is recommended to
assess AMS score only after 6 hours, to avoid confusing AMS with confounding symptoms
from travel or responses to acute hypoxia (e.g. vagal responses).
Acute high-altitude illness became a more common problem following

the popularity of mountaineering expeditions coupled with rapid uphill
transportation. The effects of HA were also seen in French and English hot-
air aerostat balloon adventurers in the 19th century. The first documented
autopsy on a HAPE patient was conducted in 1891 by Dr Wizard on one Dr
Jacottet, who collapsed while on Mont Blanc, having refused descent so that
he could make scientific measurements on the “acclimatization process”
in himself. Dr Wizard documented a “suffocative catarrh accompanied by
acute edema of the lungs”.3,9 Aleister Crowley in 1902 described the clinical
state of a climber on an expedition to K2, the second-highest peak of the
world at a height of 8,611 m in the Karakoram Ranges in a state of confusion
with bilateral pulmonary rales.3,5
The Andes of South America has an elevation ranging from 4,500 m to
5,200 m with higher peaks and mountain passes. The introduction of
railroads in the early part of the 19th century increased the speed of
ascent in these ranges which generated a series of clinical observations
of HAPE affliction.10 The Peruvian physicians especially noted an acute
form of pulmonary edema which struck down young, healthy men among
permanent HA residents who returned after 1–3 weeks in the lower regions.
Lizarraga completed an MD thesis in Spanish on the subject of HAPE in
1955.2
Charles Houston published a series of case reports in 1960 from the

skiing mountain of Aspen, Colorado. All five cases were young, able-bodied,
robust, and healthy men with no underlying disease. His index case was a
healthy 21-year-old cross country skier who developed pulmonary edema
while crossing a 3,650-m pass. X-ray chest was diagnostic with nonspecific
changes seen on an electrocardiogram. Among the remaining four patients,
there was a 26-year-old physician who undertook a self-examination and
could detect fine, moist rales on auscultation. Dr Houston speculated that
the mechanism of edema was hypoxia, pulmonary hypertension and left
ventricular failure, exacerbated by cold and exercise.11 One year later, Fred
and associates published the first hemodynamic data from two physicians,
both cases of HAPE.12 Hultgren and colleagues at the Chulec General
Hospital in Peru concluded that HAPE was associated with high pulmonary
vascular resistance (PVR) and low pulmonary artery occlusion pressure in
the presence of normal left atrial filling pressure, pulmonary capillary wedge
pressures, and reduced cardiac outputs.13
High-altitude pulmonary edema assumed greater importance following
the Sino-Indian war on the Tibetan plateau in the mid-1960s. Cold, hypoxic
troops tried to fight each other at altitudes in excess of 5,000 m. However,
Chinese troops were based lower, at 4,000 m and were well acclimatized.
They had minimal altitude morbidity. On the other hand, the Indian troops
were transported by aircraft without much acclimatization. There are two
reported series of 101 and 332 cases of HAPE during that period.14 In the
early 80s, two reports from Eastern Himalaya reviewed 85 and 55 cases,
respectively.15,16
Soldiers deployed for counter-insurgency operations are required to
live at moderate to very high altitudes. Siachen glacier is designated as
the highest battlefield in the world and lies in Northern Ladakh in the
Karakorams. Forward posts are between 5,400 m and 7,000 m (18,000–
23,000 ft). Temperatures are ranging from 15–5°C in summer to −5 to
−25°C in winter in different heights. Additional wind-chill factor is due to
blizzards at 100–160 knots. Besides the 22 confined glaciers have extremely
unstable avalanche-prone slopes and deep crevasses ranging from 12 m
(40 ft) in depth to practically bottomless ones. The soldiers are exposed
to severe environmental stresses such as cold temperature, low humidity
(relative humidity 10–50%), increased ultraviolet radiation, and decreased
atmospheric pressure (which varies from 0.74 to 0.5 atm). Most of the
soldiers are from the plains and so are subjected to strict acclimatization
schedules (Table 4). Indian investigators have had extensive experience
with various aspects of AHAI with large cohort published studies on
soldiers.14-21
Table 4: Indian Armed Forces Acclimatization Schedule.17,18

Stage No. of days Activities
First stage: 6 Days 1–2: Rest except short walks about barracks,
2,700–3,600 m no climbing
(8,900–11,800 ft) Days 3–4: Walk slowly for 1.5–3 km (1–2 miles),
avoid steep climbs
Days 5–6: Walk up to 5 km (3 miles) and climb
slowly up to 300 m (1,000 ft)
Second stage: 4 Days 1–2: Walk slowly for 1.5–3 km (1–2 miles),
3,600–4,500 m avoid steep climbs
(11,800–14,700 ft) Day 3: Walk slowly and climb up to 300 m (1,000 ft)
Day 4: Climb 300 m (1,000 ft) with equipment
Third stage: 4 Days 1–2: Walk slowly for 1.5–3 km (1–2 miles),
>4,500 m (14,700 avoid steep climbs
ft) Day 3: Walk slowly and climb up to 300 m (1,000 ft)
Day 4: Climb 300 m (1,000 ft) with equipment
PHYSIOLOGY AT HIGH ALTITUDE

Ventilation
Within the First Few Hours of High-Altitude Exposure
• Low-ambient oxygen in HA increases ventilation by stimulating the
peripheral chemoreceptors in the carotid body. This is called as hypoxic
ventilatory response (HVR). The resultant increase in respiratory rate
through the central respiratory center in the medulla increases the
partial pressure of oxygen in the arterial blood (PaO2) and improves
oxygen delivery but concomitantly lowers the partial pressure of carbon
dioxide in the arterial blood (PaCO2). This response starts at an altitude
as low as 1,500 m.22,23
• This increase is the respiratory rate is genetically determined,24 but is
not a reliable predictor of venerability to AHAI.3,5,22
• Factors increasing the response include general metabolic (e.g. caffeine)
and respiratory (e.g. progesterone) stimulants.2,24
• The response is depressed by respiratory depressants, such as alcohol
and lack of sleep.22,25,26
• Prior physical conditioning has no reported effect on HVR.23
After 4–7 Days after Residence at the Same Altitude

• The acute increase in ventilation washes out CO2, producing hypocapnia
and respiratory alkalosis. This inhibits the central respiratory center,
causing the respiratory rate to slow.12,16
• Metabolic compensation for the respiratory alkalosis in the form of

an increase in renal bicarbonate excretion helps restore blood and
cerebrospinal fluid (CSF) pH which, in turn, increases the rate and depth
of respiration.22,25
• This decrease in plasma bicarbonate concentration continues and the
secondary rise in the ventilation continues.5,22,27 The steps are magnified
with each successive increase in altitude.
Circulation
Systemic Circulation5,26,28
• The increase in sympathetic activity at HA causes a minimal increase
in blood pressure, a moderate increase in resting heart rate and cardiac
output and an increase in venous tone. The resting heart rate returns to
baseline values with acclimatization except at extremely HAs.
• Bicarbonate diuresis, intravascular fluid shift, and aldosterone suppression
produce a decrease in plasma volume with resultant low stroke volume.
• Reduction in myocardial oxygen demand due to reduced maximal heart
rate and cardiac output prevents ischemic changes.23,29
Pulmonary Circulation
• Pulmonary arterial (PA) pressure shows an increase secondary to
pulmonary vasoconstriction due to HPV. This pulmonary arterial
hypertension (PAH) is aggravated by exercise, with pressures almost
reaching systemic levels.5,13
• In spite of this, no evidence of left ventricular dysfunction or abnormal
atrial/ventricular filling pressures have been demonstrated at rest.29
• Pulmonary capillary wedge pressure is low.2,25
• Cardiac output remained adequate partially due to compensatory
increased atrial contraction.5,25,28
Echocardiographic findings usually demonstrate decreased left ventricular
stroke volume, with mild right ventricular enlargement. Despite the mild
dilatation in the presence of pulmonary hypertension, the right ventricular
function remains intact.22,23
Cerebral Circulation
Cerebral oxygen delivery depends on the balance between hypoxia-induced
cerebral vasodilation and hypocapnia-induced cerebral vasoconstriction.
When PaO2 is <60 mm Hg (i.e. at altitude >2,800 m), impairment in cerebral
autoregulation occurs which causes the cerebral blood flow (CBF) to
increase, despite the hypocapnia.
Blood5,11,13,22,25,26,29,30
Hematopoietic response to altitude is an important part of the acclimatization
process.
• Hypoxia causes release of erythropoietin from the kidneys which
stimulate red blood cell (RBC) synthesis.
• This rise in erythropoietin can be detected within 2 hours of ascent to
HA. Within 3–5 days, immature nucleated RBC can be seen in peripheral
blood films.
• The hemoglobin concentration shows an initial increase due to a decrease
in plasma volume secondary to diuresis.
• Acclimatization leads to an increase in both plasma volume and RBC
mass.
• Oxygen-hemoglobin dissociation curve shifts to the left due to
hyperventilation-induced respiratory alkalosis. A concomitant increase
in red cell 2,3-diphosphoglycerate (2,3-DPG) tends to shift the curve to
the right. Resultant is a small increase in P50 value with a decrease in
oxygen-hemoglobin affinity. This makes more O 2 available to the tissues.
Tissues14,31,32
The following compensatory changes occur in the tissues:
• Hypoxia-inducible factor-1α stimulates vascular endothelial growth
factor (VEGF) production. This increases angiogenesis with a resultant
increase in blood flow and oxygen delivery to the tissues.
• Increase in number of mitochondria with an increase in oxidation.
• Increase in myoglobin.
• Increase in tissue cytochrome oxidase.
PATHOPHYSIOLOGY
High-altitude pulmonary edema is a high pulmonary capillary permeability
type of edema occurring due to maladaptive responses to the hypoxia
encountered at HA. The initiating event is PAH with mean PA pressure
in excess of 35–40 mm Hg. This is postulated to be due to the following
concomitant factors:
• Alveolar hypoxia and poor ventilatory response.
• Increase in sympathetic tone with exaggerated and uneven HPV.
Specific segmental and subsegmental capillary beds with relatively
less vasoconstriction are disproportionately exposed to elevated
microvascular pressures (>20 mm Hg) that arise from the elevated mean
PA pressure.
• Development of pulmonary hypertension due to inadequate pro
duction of pulmonary vasodilator, endothelial nitric oxide (NO),
and overproduction of endothelin-1 which is an extremely powerful

vasoconstrictor, also involved in vascular remodeling.
Many of these factors are genetically determined.22,23,26,27,29
The resultant patchy PAH results in failure of the alveolar-capillary
barrier. This leads to leakage of large protein molecules and fluids into the
alveolar space, resulting in high-permeability, noncardiogenic pulmonary
edema (“stress failure”). Eventually, basement endothelial and epithelial
cell membranes are disrupted, leading to alveolar hemorrhage.2,13,22
A striking feature of HAPE is the rapid reversibility of this process with
descent or sometimes simply the administration of oxygen. Pulmonary
vascular resistance returns to normal within days after descent to low
altitude.
EPIDEMIOLOGY AND RISK FACTORS

The reported incidence of HAPE ranges from an estimated 0.01% of
skiers traveling from low altitude to Vail, Colorado ski resort (2,500 m), to
15.5% of Indian soldiers rapidly transported to altitudes of 3,355–5,940 m
(approximately 11,000–18,000 ft).2,10,11,21
High-altitude pulmonary edema is divided into three types:
1. Classic HAPE: Involving acute ascent of those normally residing at low
altitude.
2. Reentry HAPE: Involving re-ascent of those normally residing at HA after
a stay at low altitude.
3. Late-onset HAPE: New entity documented in Ladakh with manifestations
of HAPE occurring 7–65 days after the induction to HA.
Another category has been suggested for children living at altitude who
develop pulmonary edema with respiratory infection but without a change
in altitude.32
Risk Factors
• Rapid ascent profiles are recognized as a risk factor for HAPE. All
individuals ascending at greater than 500 m a day above the level of
3,000 m are at increased risk for AHAI. Climbers assigned to a 19-day
ascent, compared with a 15-day ascent, while climbing Muztagh Ata
(7,546 m) had significantly fewer symptoms and a greater proportion
climbed higher.33 In addition, those who rapidly ascend over 3,500 m
in 1 day are at risk of HAPE, for example when using air travel to high-
altitude destinations (e.g. La Paz, Bolivia).34
• The incidence of AHAI is also related to maximum altitude ascended.
AMS typically develops at altitudes > 2,500 m, HAPE > 3,000 m, and
HACE > 4,000–5,000 m, although susceptible individuals can be affected
below these altitudes.
• Pre-existing conditions or anatomic abnormalities that lead to increased

pulmonary blood flow, pulmonary arterial hypertension, or increased
pulmonary vascular reactivity may predispose to HAPE, even at altitudes
below 2,500 m. Some of the conditions which may predispose to HAPE
are:
▪▪ Primary pulmonary hypertension (PPHN).
▪▪ Congenital absence of one pulmonary artery.
▪▪ Left-to-right intracardiac shunts, such as atrial septal defects (ASDs)
and ventricular septal defects (VSDs).
▪▪ Hyperresponsive pulmonary circulation to hypoxia or exercise at sea
level.
• Other factors associated with an increased incidence of HAPE include:27,28
▪▪ Male gender.
▪▪ Cold ambient temperatures.
▪▪ Pre-existing respiratory infection.
▪▪ Vigorous exertion.
• Genetics clearly plays an important role in the risk of HAPE, as seen
by the marked variance in individual susceptibility and the higher rates
of recurrence among some individuals. Individuals who are prone to
develop HAPE may also develop flash pulmonary edema at sea level
if exposed at any inciting event. However, HAPE genetic studies are
conflicting and no clear conclusions can be derived.
Healthy Tibetans are protected against AMS and maintain good adaptation
to HA, even after a long period of stay at low altitudes. They have been found
to have a significantly higher plasma concentration of NO by-products.
Impaired NO synthesis occurring with NO-synthase polymorphisms has
been postulated as a genetic cause of HAPE susceptibility.24,26,31
Genetic and epigenetic variation in the genes that code for hypoxia-
inducible factors, transcription factors, heat shock protein (HSP 70), may alter
expression of these factors in response to low cellular oxygen concentrations.
This may also be responsible for variation in individual susceptibility to
HAPE.
Genes for the pathways for renin-angiotensin-aldosterone and pulmonary
surfactant proteins A1 and A2 have also been studied. Variation in alveolar
fluid clearance related to sodium channel phenotype, aquaporin-5 may also
be implicated.35
Patent foramen ovale (PFO), deserves a special mention. PFO was
found in 25–30% of individuals in an autopsy study and in a community-
based transesophageal echocardiography (TEE) study ranging from 34.3%
during the first three decades of life to 25.4% during the 4th through
8th decades and to 20.2% during the 9th and 10th decades.36,37 A rising
PVR during HPV may reverse the direction of blood flow, shunting blood
from right to left and further exacerbating hypoxemia. PFO is four times
more common among HAPE-susceptible individuals. Larger PFOs correlate

directly with increased arterial hypoxemia, and a trend toward an increased
risk of developing HAPE. Whether PFO contributes to HAPE or is merely a
marker of increased vascular reactivity and susceptibility remains unknown.
However, there is currently no indication for preventively closing PFO in
HAPE-susceptible persons.2,12,13,38
CLINICAL PRESENTATION3-5,11,12,14
High-altitude pulmonary edema generally begins with a subtle,
nonproductive cough, dyspnea on exertion, especially on walking uphill.
Initial symptoms typically appear within 2–4 days after arrival at HA or a
new altitude and are easily mistaken for a benign upper respiratory tract
infection or attributed to normal breathlessness at altitude or exhaustion.
Occasionally, HAPE develops precipitously. This occurs more often at night
or after severe exertion. Patients of HAPE may have symptoms of AMS
initially before becoming breathless. HAPE almost never develops after a
week at the same altitude.
As HAPE progresses, dyspnea becomes noticeable at rest and severe with
any attempt at exertion. Even walking on a level surface becomes an effort.
A cardinal clinical feature of HAPE is the rapid worsening of the presenting
dyspnea on exertion to dyspnea at rest. As symptoms progress, the initial
dry cough becomes productive and frothy with frank blood at times. Severe
hypoxemia may cause drowsiness or concomitant HACE with ataxia and
altered consciousness generally without neurological deficit. Persons with
genetic or acquired (e.g. carotid endarterectomy, neck radiation) blunted
carotid body function may present without respiratory symptoms and
instead with drowsiness, confusion and other central nervous system (CNS)
symptoms and findings.
The examination usually reveals tachycardia, tachypnea, and low-grade
fever (up to 38°C). Central cyanosis may be appreciated and inspiratory
crackles are more prominent in the right middle lobe initially. Auscultation
of the right middle lobe is best performed at the mid-lateral chest wall.
As severity of HAPE increases, there is worsening of breathlessness and
tachycardia and the inspiratory crackles become diffuse and bilateral with
development of an accentuated pulmonary component of 2nd heart sound
and features of right heart failure.
The diagnosis is primarily clinical, requiring at least two symptoms and
two clinical signs as given in Table 2. About 52% of patients with HAPE
have concurrent AMS and 14% have concurrent HACE.2,23
Pulse oximetry is a useful tool to not only to document hypoxia and to
monitor response to therapy but also to assess the degree of acclimatization.
SpO2 is low, being lowest on the first day at HAA, being at least 10 points
lower than expected for the altitude, and absolute values may be as low as
40–50%. Values rise over 4 days to a near-maximum value, usually 3–5 points
higher than day 1. In a study of HAPE patients at an altitude of 4,559 m,
observed values for SaO2 was 48±8% and for PaO2 23±3 mm Hg as against
healthy control values of 78±7% and 40±5 mm Hg, respectively.39
Both the clinical status and SpO2 rapidly correct (usually within 10–15
min) with supplemental oxygen and this in the setting of a severe infiltrative
lung process seen on radiograph is virtually pathognomonic for HAPE,
as this does not occur with other similar clinical pulmonary conditions
[e.g. pneumonia, acute decompensated heart failure (ADHF)]. However,
expected SpO2 values vary with a number of factors, including the altitude,
degree, and rate of acclimatization, patient’s hypoxic ventilatory drive,
and method of measurement (e.g. variation among pulse oximeters), and
therefore should be interpreted carefully.40
A prospective cohort study of all troops reporting to a transit camp of the
Indian Army for the first stage of acclimatization (see below, “Prevention”)
located at a height of 3,142 m was conducted over a 3-month period. The
participants were divided into two groups—those troops reporting to HAA
for the first time (first entry; FE) and those reporting after absence of
more than 10 days but less than 30 days from HAA (reentry; RE). A total
of 278 transients were FE and 244 RE were included. Apart from routine
epidemiological data recording, monitoring of pulse, blood pressure, and
SpO2 were done on Day 1 and Day 6. Only 7 FE and 2 RE troops (4.70%) were
found unfit to proceed to higher altitudes when subjected to a brisk walk
of 1 km after the period of acclimatization. Tachycardia with a SpO2 below
90% by digital pulse oximetry were the parameters found to be statistically
significant as an indicator to declare a person as not fully acclimatized or
otherwise.41
A study on a group of climbers at 3,600 m during an expedition to the
Bolivian Andes found that acclimatized subjects could maintain their SpO2
during prolonged exercise better than unacclimatized subjects. The authors
concluded that two parameters were statistically significant as an indicator
to declare a person as not fully acclimatized or otherwise—tachycardia
and oxygen saturation below 90% by digital pulse oximetry. Although
expected values can vary widely in normal individuals at any given altitude,
comparing SpO2 measurements with others in the same group who arrived
at altitude together can help to establish relative “normal” values.42
INVESTIGATIONS
None of the investigations are specific for diagnosis, that being based on
clinical suspicion, history, and physical examination.
Laboratory tests: No laboratory test is specific to diagnose HAPE. Mild

leukocytosis is present and brain natriuretic peptide (BNP) and related tests
(e.g. pro-BNP) may be slightly elevated at HAs. Troponin may be elevated
in the setting of HAPE associated with right heart strain.
Electrocardiogram (ECG) is nonspecific with sinus tachycardia, right
bundle branch block pattern, right axis deviation, or right heart strain.
Chest radiography is useful and reveals characteristic patchy alveolar
infiltrates, predominantly in the right central hemithorax, which become
more confluent and bilateral as the illness progresses. However, in some
cases, the infiltrates may start in the left lung. The picture is similar to that of
noncardiogenic pulmonary edema. The only difference noted is the milder
clinical profile and the steady, rapid improvement with oxygen therapy.38,43
Computerized tomography (CT) of the chest reveals a patchy
lobular ground-glass appearance and consolidative opacities, reflecting
heterogeneous alveolar filling.
Echocardiography can demonstrate increased PA pressure and sometimes
right heart dysfunction and paradoxical septal motion.
Ultrasound of the chest is a highly-sensitive and semiquantitative means
of detecting increased extravascular lung water (EVLW). If traditional chest
radiography is unavailable (e.g. at a remote clinic or in the field), HAPE can
be confirmed by the presence of ultrasound lung comets (ULCs). While the
quantity of ULCs corresponds closely to clinical and oximetry findings, it
is not known what number of ULCs is an appropriate diagnostic threshold
for HAPE, as opposed to subclinical pulmonary edema. Nevertheless, the
technique for identifying ULCs is easily performed and may be useful in the
proper clinical setting, such as when the cause of dyspnea is unclear despite
a careful history and physical examination.
Limitations of ultrasound include:44
• Lack of specificity: Ultrasound cannot differentiate HAPE from cardiogenic
pulmonary edema and other causes of increased EVLW.
• Ultrasound findings may not be clinically relevant at altitude, as clinically
insignificant ULCs are commonly seen in recreational climbers who are
asymptomatic and do not develop HAPE, especially older persons.15,19
• Ultrasound findings may not add to what is already known from
examination findings and oximetry.
DIFFERENTIAL DIAGNOSIS
High-altitude pulmonary edema can be confused with pneumonia,
pulmonary embolism, ADHF, acute coronary syndrome, reactive airway
disease, and exercise-associated hyponatremia (EAH).26,30 Rapid response
over hours to oxygen therapy strongly suggests the diagnosis of HAPE in
this setting. Rapid improvement with descent is another important clue to

the diagnosis of HAPE.
TREATMENT
General Management2,5,11,22,29,38,42,45-47
Aim of management is an urgent reduction of PA pressure. This can be
achieved either by nonpharmacologic interventions or pharmacologic inter
ventions.
Nonpharmacologic Interventions
Nonpharmacologic interventions include the following:
• Limiting physical exertion and cold exposure: Strenuous physical exertion
and cold stress both elevate PA pressure and can exacerbate HAPE.3 A
patient with HAPE should not carry a pack while descending.
• Evacuation to a lower altitude: Immediate descent is not mandatory in
all settings. Its usefulness varies depending upon a number of factors,
including severity of illness, altitude, available treatments, setting,
clinician experience, and patient factors. In remote high-altitude settings
where supplemental oxygen is unavailable, descent should begin as soon
as HAPE is suspected.2,5 HAPE can progress rapidly and the opportunity
for evacuation may be lost if there is any delay. At higher elevations
(>4,000 m), the descent is mandatory, in part because of the risk of
developing HACE. Ideally, immediate evacuation is undertaken to a
hospital below 3,000 m that is capable of providing high-flow oxygen.
Nevertheless, in practice, scores of HAPE patients are treated successfully
in remote clinics or base camps with modest descent and rest, sometimes
in combination with hyperbaric therapy, low-flow supplemental oxygen,
and medication. Many remote clinics are located only 500–1,000 m
below the elevation of HAPE onset. When HAPE is diagnosed early
and treated, many climbers go on to re-ascend slowly after 2–3 days
of recovery. Recurrence of HAPE in such circumstances has not been
reported. Severe cases require evacuation to a medical facility at lower
elevation.
• Simulating descent using hyperbaric therapy: In remote settings, light weight
portable hyperbaric chambers (“HAPE Bags”) bags may be lifesaving,
particularly when supplemental oxygen is unavailable or in short supply.
These devices, although costly, are well-suited to mountaineering and
trekking expeditions at HA, where compressed oxygen cylinders are too
heavy and bulky to transport and are difficult to maintain.46
These hyperbaric chambers should not be used in cases of mild AMS for
either prevention or treatment. Pressurized bags are NOT designed to
treat mild symptoms of AMS or to facilitate continued ascent just to

proceed the next day without adequate acclimatization. In the case of
mild symptoms, the advice is to slow the ascent rate and consider taking
a rest day. Use that time to retreat from altitude.
A HAPE bag is a cylindrical inflatable pressure bag large enough to
accommodate a person. It is made up of medium-heavy impermeable
coated fabric with an air-proof zipper. Various valves are integrated to
facilitate the ease of operation and safety. The bag is sealed and inflated
with either a foot pump or a power-operated compressor with rapid
decrease in the “effective altitude” within minutes to 1,000–3,000 ms
(3,281–9,743 ft). The pressure inside the HAPE bag ranges from 105 mm Hg
to 220 mm Hg with an approximate volume of 600 L to accommodate an
average person even with multiple layers of clothing. There is a preleak
control valve which bleeds approximately 20 L/min in order to avoid
build-up of carbon dioxide. Patients typically are treated in 1-hour
increments and then are reevaluated. While on a HAPE bag, the patient
should never retreat unaccompanied.
• Oxygen: Supplemental oxygen is first-line management for HAPE.
Relieving hypoxemia is the most effective method of reducing PA
pressure, reversing capillary leak, and protecting the brain and other
organs. Supplemental oxygen immediately increases PaO2 and reduces
both the respiratory rate and pulse. While some studies have shown that
oxygen combined with medication is more effective than oxygen alone
in lowering PA pressure, clinical outcomes were not assessed.15,40,45
• A common regimen in North American hospitals near ski resorts
(elevation approximately 2,500–3,000 m) is to treat with high flow
supplemental oxygen by nasal cannula or face mask for several hours
until the patient’s oxygen requirement is ≤3 L/min with the SpO2
maintained at 90% or higher. If the patient is clinically improved and
appropriate for outpatient therapy, he or she may be sent home with
an oxygen concentrator to be used continuously and strict instructions
to rest. The patient’s condition and SpO2 are rechecked daily until an
ambulatory SpO2, measured while the patient breathes room air, is ≥90%.
At this point, supplemental oxygen is discontinued and the patient is
advised to slowly return to activity over the following 1–3 days. Descent
is not mandatory but is always an option in this setting.42
Positive airway pressure: The use of a breathing mask providing expiratory
positive airway pressure (EPAP) has been shown to improve gas exchange
in HAPE, and may be useful as a temporizing measure.35 A similar effect
may be achievable by having the patient breathe through pursed lips.
Continuous positive airway pressure (CPAP) is used in some ski resort
clinics with anecdotal success. Nevertheless, no study has established that
CPAP improves clinical outcome in patients with HAPE. A CPAP helmet has
been used in the field.36
Pharmacologic Interventions17,44-49
Interpretation of studies conducted for the prevention and treatment of
HAPE is problematic as selection bias for inclusion of subjects who are
known to be highly susceptible to HAPE cannot be ruled out. Extrapolation
of the results to a general population needs validation.
Nifedipine: This is a nonspecific calcium channel blocker that acts by
reducing PVR and PA pressure, as well as systemic vascular resistance and
blood pressure. It also slightly improves PaO2. Recommended dosages vary,
but a common regimen is to give 20 mg three times a day, preferably as slow-
release tablets. It is recommended as the first-line adjunct in Wilderness
Medical Society guidelines,49 although a recent study in HAPE recovery
reported no additional benefit if descent and oxygen supplementation
is adequate.47,49 Short-acting preparations of nifedipine should be avoided
in view of the risk of cerebral hypoperfusion.17
Precautions: It is normally well tolerated and does not cause significant
hypotension in previously healthy persons. Clinicians should give or be
prepared to give isotonic intravenous fluid (e.g. normal saline) to any
critically ill HAPE patient who may be intravascularly depleted and is
receiving nifedipine.
Phosphodiesterase-5 (PDE-5) inhibitors: Both tadalafil and sildenafil may
be the effective adjunct treatment for established HAPE when neither
oxygen nor descent is an available option. These augment the pulmonary
vasodilatory effects of NO by blocking the degradation of cyclic guanosine
monophosphate (cGMP), the intracellular mediator of NO. Nitric oxide is a
potent pulmonary vasodilator and reduces HPV and pulmonary hypertension
in HAPE.31 These drugs may have advantages over nifedipine because they
lower PA pressure with less risk of lowering systemic blood pressure.18,47,50,51
Dose of tadalafil is 10 mg twice daily and that of sildenafil is 50 mg three
times a day.
Dexamethasone: The mechanism of action of dexamethasone remains
unclear. It may involve upregulation of both NO production and of alveolar
epithelial membrane sodium channels and sodium-potassium ATPase.47,51
This is usually reserved for treatment of AMS or HACE, which may coexist
with HAPE.
Ineffective or contraindicated therapies: Diuretic therapy, nitrates, beta-
blockers, and morphine are not currently recommended because of limited
trial data in the susceptible population.18,47
To summarize, the key principle in successful treatment of HAPE is a
strong clinical suspicion. Descent (simulated or actual) and supplemental
oxygen are often effective alone and appear to be superior to any
pharmacologic therapy. In isolated mountain settings, oxygen may be
limited, precluding its use as the sole treatment. Hyperbaric therapy is

commonly combined with pharmacotherapy and supplemental oxygen,
if available. In the hospital setting, the elevation is generally lower and
high-flow oxygen is readily available. Hyperbaric therapy is not practical or
necessary in such hospitals or clinics.
No trials have been performed in patients with HAPE that directly
compare treatment using oxygen and descent with pharmacologic therapy.
Nevertheless, the clinical outcomes reported in studies in which nifedipine
alone (see below) was used for treatment were poor compared with those
involving oxygen and descent without medication.23 Pharmacotherapy
(nifedipine) was of no added clinical benefit in patients who received
oxygen and descent.29
PREVENTION
Acclimatization: A three-stage acclimatization schedule is recommended by
the Indian Army (see Table 3):52
• Stage I acclimatization lasts for 6 days for altitudes ranging from
2,700 m to 3,600 m.
• Stage II and stage III require an additional 4 days each, for altitudes
3,600 m to 4,500 m and >4,500 m.
• During reentry to HAA, after 10–30 days of absence from HAA, 4 days
at each stage need to be spent.
• After a break of more than 30 days, full acclimatization schedule as fresh
inductees needs to be followed.
Gradual ascent remains the primary method for preventing all forms of
HA illness, including HAPE. Those susceptible to HAPE should not ascend
greater than 300 m per day.
Pharmacological Prophylaxis18,47,49-51
• For patients with no history of medical problems at HA or of pulmonary
hypertension, the risk of HAPE is low and routine prophylaxis is not
warranted.
• In individuals at high-risk, particularly those with a history of HAPE,
pharmacologic prophylaxis may be prudent, especially when the time
does not allow for adequate acclimatization.
Nifedipine is the drug of choice for prophylaxis against HAPE and is
recommended only in high-risk individuals and only when acclimatization
is not possible. It has been reported to reduce the incidence of HAPE from
63% to 10% when ascending over 4,500 m. Ideally, treatment is started 24
hours prior to ascent and continued for 5 days at the destination altitude
or until descent below 2,500 m is completed. In higher-risk scenarios,
treatment may be continued for a longer period.
• Both tadalafil and sildenafil have been shown to be effective as

prophylaxis for HAPE. Optimal doses have not been established. Tadalafil
10 mg twice daily has similar efficacy to nifedipine in HAPE prevention.
However, a recent randomized controlled trial testing sildenafil for HAPE
prophylaxis reported an increase in incidence and severity of AMS.
Sildenafil has shorter dosing intervals because its half-life is 4–5 hours;
tadalafil’s half-life is 17 hours.50
Dexamethasone: Glucocorticoids act through an improved alveolar fluid
absorption and may have a role in prophylaxis, but to be effective must
be taken prior to ascent. In one randomized trial of 29 individuals with
a history of HAPE, none of the 10 participants given dexamethasone
prophylaxis (8 mg every 12 hours) developed HAPE during a rapid
ascent from 490 m to 4,559 m with an overnight stay. Prophylaxis with
dexamethasone has the added advantage of preventing AMS/HACE,
whereas nifedipine and the PDE-5 inhibitors have no such effect.18
• Salmeterol should be considered only as an adjunct treatment
to nifedipine in high-risk individuals with a clear history of recurrent
HAPE. Salmeterol prevented HAPE in 50% of subjects in one small study
and thus appears less effective than other agents.47,48
• Acetazolamide is a reasonable medication for HAPE prophylaxis, but
formal studies are lacking.
CONCLUSION
Exposure of human beings to altitude above 1,500 m puts them at risk of
developing acute HA illnesses such as AMS, HAPE, and HACE. This happens
primarily due to fall in barometric pressure resulting in low atmospheric
oxygen pressure which affects physiological parameters. Hypoxia affects
ventilation, systemic, pulmonary, and cerebral circulation. The maladaptive
response to hypoxia causes alteration in ventilation and circulation causing
high permeability HAPE. There are various modifiable and nonmodifiable
risk factors for the development of HAPE. The diagnosis of HAPE is clinical.
Pulse oximetry is a useful tool not only to document hypoxia and to monitor
response to therapy but also to assess the degree of acclimatization.
Treatment of HAPE is descent to lower altitude (actual or using hyperbaric
chamber) and supplemental oxygen therapy. For prevention of HAPE, one
should follow a three-stage acclimatization schedule recommended by the
Indian Army and pharmacologic prophylaxis for high-risk individuals.
KEY POINTS
• High altitude illnesses can result in sudden morbidity and at times mortality
in apparently healthy individuals.
• The common factor among HA illnesses is hypobaria resulting in hypoxia.
The hypoxia leads to abnormal physiological responses in susceptible

individuals.
• Primarily, hypoxia causes pulmonary arterial hypertension which in turn
causes high permeability pulmonary edema.
• Rapid ascent to HA especially over 3,500 m in 1 day is the biggest risk
factor for developing high-altitude pulmonary edema.
• Pre-existing conditions like cold ambient temperatures, male gender,
physical exertion, and genetics are associated with an increased incidence
of HAPE.
• High-altitude pulmonary edema generally begins as nonproductive cough,
dyspnea on exertion, and difficulty walking uphill. Examination reveals
tachycardia, tachypnea, and respiratory crackles.
• Pulse oximetry is a useful tool to detect hypoxemia and to monitor
response to oxygen therapy.
• Treatment of HAPE includes limiting physical exertion and exposure to
cold, evacuation to lower altitude, and oxygen administration.
• Gradual ascent remains the primary method for preventing all forms of
HA illnesses. A three-stage acclimatization schedule recommended by the
Indian Army is most appropriate.
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CHAPTER
22 Infection Prevention in the

Operating Room
Neha Agrawal
INTRODUCTION
Operating room (OR) is one of the most critical areas of any healthcare
organization in which infection prevention and controlled practices are
challenging for administrators as well as clinicians. Various studies have
shown the cross-contamination in the OR as a result of certain problematic
practices by the anesthesia providers,1 breach in engineering controls or
improper environment cleaning and disinfection. Although inoculation
of the operative site by the endogenous patient flora intraoperatively
is the major cause of surgical site infections (SSI), contaminated OR
environment has been identified as an important source of SSI in some
settings.
Surgical site infection is a significant cause of morbidity and mortality
and is responsible for 38% of hospital-acquired infections in surgical
patients.2 Various endogenous (patient-related) and exogenous factors
influence the risk of SSI. Malnutrition, old age, coexistent infection,
and diabetes are patient-related factors whereas external risk factors
are multifaceted. The quality of preoperative skin preparation, type, and
duration of surgery, timing, adequacy, and appropriateness of antibiotic
prophylaxis, surgeons’ skill, insertion of implants, anesthesia provider’s
practices, inadequate sterilization of surgical instruments are the external
risk factors.3 Besides this, OR quality has a significant association with
surgical wound infection4 which is affected by OR design, layout, heating,
ventilation, and air conditioning (HVAC), management, and behavior of
healthcare workers.
Hence, it is imperative that appropriate measures are taken to prevent
infection in OR beginning from designing to routine intervention, the
involvement of clinicians, staff and senior leaders for implementation of
those infection prevention strategies.1,4-14
Infection Prevention in the Operating Room 329
INFRASTRUCTURE MEASURES
Operating Room Complex Design
Location
Operating room complex should preferably be located where the patient
movement is minimal and hence, the ground floor location should be
avoided as there is maximum traffic of patients.
Zoning of Operating Room Complex

As an infection control measure, OR complex layout has four zones:
1. Protective zone: Change rooms, staff rooms, preoperative area, recovery
beds, stores, and records lie in the protective zone.
2. Clean zone (semisterile zone): After the protective zone and before
sterile zone lies the clean zone. All personnel need to change in
OR dress before entering the clean zone. The scrub station, sterile
disposable storing areas lie in this zone.
3. Sterile zone: The main operating area (OR) lies in this zone.
4. Disposal zone: All unsterile items from the OR should come out
through a separate exit (other than the entry of OR) directly into the
disposal zone.
Heating Ventilation and Air Conditioning System

Operating room air quality is maintained by an HVAC system which is an
important determinant of surgical wound contamination intraoperatively.
The HVAC system consists of the following components:5
• Air handling unit (AHU)
• Inflow and outflow ducts
• Air conditioning compressor
• Air blower
• Pre-high efficiency particulate air (HEPA) filters (3 and 5 µ filters)
• Laminar airflow (LAF) plenum
• Terminal 0.3 µ HEPA filter.
The AHU should be operational round the clock to maintain the
air quality. A variable flow device if installed reduces the electrical load
consumption and regulates the air exchanges in the OR without the cooling
effect. Cleaning of filters needs to be done on a regular basis. Prefilters can
be reused. The terminal 0.3 µ HEPA filter needs to be changed when the
particulate counts and air qualities are not up to the required standards.5
The maximum allowable particle concentration of ISO Class 4, 5 and 6
rooms as per ISO 14644-1:201515 cleanroom classification is given in Table 1.
Table 1: Maximum allowable particle concentration of ISO Class 4, 5, and 6 as per

ISO 14644-1:2015.15
Maximum allowable concentration (particles/m3) for particles equal to and
ISO Class bigger than below-mentioned sizes
number O.1 µm 0.2 µm 0.3 µm 0.5 µm 1 µm 5 µm
4 10,000 2,370 1,020 352 83 –
5 100,000 23,700 10,200 3,520 832 293
6 1,000,000 237,000 102,000 35,200 8,320 2,930
In 2008, the American National Standards Institute, the American Society

of Heating Refrigerating and Air Conditioning Engineers and the American
Society for Health Care Engineering of the American Hospital Association
jointly developed the ventilation and air conditioning guidelines which was
further revised in 2017.16 Some features of guidelines state the requirement
of positive pressure within the OR as compared to adjacent areas, to have
at least 20 air changes/h (4 or more should be fresh air). Average OR
temperature range is from 20°C to 23°C, except for certain type of surgical
procedure, e.g. cardiac (17°C) and pediatric surgeries (27°C).17 Centers for
Medicare & Medicaid Services (CMS) recommend separate temperature
controls for each OR.18 Recently, there has been a change in requirements of
relative humidity levels in ORs. Instead of the requirement of maintenance
of more than 35% relative humidity, it has now been recommended to have
relative humidity between 20% and 60%.18
National Accreditation Board for Hospitals & Healthcare Providers
(NABH) has also given air conditioning guidelines for OR. The latest NABH
guidelines6 of air conditioning in OR are summarized in Table 2. In addition,
NABH guidelines recommend dedicated AHU for each OR. In case there is
one AHU for multiple ORs, there should be backup OR so that surgeries can
be performed in these ORs in case of breach of sterility in ORs with single
AHU. AHU should be located where there are no source of contamination,
e.g. vehicle parking area, DG exhaust hoods, and lab exhaust vents. The
window and split AC should not be used in any type of OR. Cleaning of pre-
HEPA filters is recommended at the interval of 30 days. NABH recommends
the validation of the system bi-annually and as per ISO 14644 standards.6
Table 3 mentions the checks during the validation process.
Although above-stated guidelines have mentioned the use of LAF
system to minimize the contamination of the surgical field with airborne
microorganisms and its contribution in the reduction of SSI, few publications
have questioned the use of LAF. Further to this, Jain and Reed reviewed
contemporary laminar airflow handling systems and made recommendations
for effective laminar airflow use.19 Table 4 lists these recommendations.
Table 2: National Accreditation Board for Hospitals and Healthcare Providers (NABH) guidelines for air conditioning in OR.
Air filtration
Minimum air
changes per Positive HEPA Air quality at Relative
hour Air velocity (FPM) pressure Pre-HEPA filter filter grill level Temperature humidity
Type of OR
Total Fresh Pattern FPM Pascal 10 µ 5µ 0.3 µ
Type A 20 4 Unidirectional 25–35 2.5 90% 99.97% 99% Class 100/ 21°C ± 20–60%
(erstwhile and downward ISO Class 3°C (joint ideal 55%
super-specialty on OR table 5 (at rest replacement
OR), e.g. neuro- condition) 18°C ±2°C)
sciences OR,
orthopedic
(joint
replacement),
cardiothoracic
and transplant
surgery OR
Type B 20 4 Unidirectional 25–35 2.5 90% 99.97% May be Class 1000/ 21°C ±3°C 20–60%
(erstwhile and downward provided ISO Class ideal 55%
general OR) on OR table 6 (at rest
condition)
(FPM: feet per minute; HEPA: high-efficiency particulate air; OR: operating room)
Table 3: Biannual OR checkpoints during validation as per the National Accreditation

Board for Hospitals and Healthcare Providers (NABH) 2018 guidelines.6
Temperature
Humidity
Air change rate
Air velocity at the outlet of terminal filters
Pressure differential levels
HEPA filters efficiency
(HEPA: high-efficiency particulate air; OR: operating room)
Table 4: Recommendations for effective laminar airflow (LAF) use.19

Element Action
Operating room (OR) door opening after Minimal
the start of surgery
Number of staff in OR Restrict
OR light position Should not be directly over the surgical
site
Opening of instrument trays and At the time of the beginning of surgery
implants
Air warming appliance Blanket or resistive heating mattress
preferred
Duration of C-Arm use within the Should be limited
ultraclean enclosure
Physical actions near the surgical field Minimal
and instrument trays
Position of surgeon Should not cut off vertical airflow stream
Changing of gloves Not near surgical site or instrument trays
Periphery of the ultraclean enclosure Keep clear
Water Distribution System

Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Acinetobacter spp.,
etc. cause healthcare-associated infections through the water distribution
system in hospitals. Taps are the common source of P. aeruginosa. Hence,
water used in dental surgery and for surgical hand scrubs in OR needs strict
quality control to prevent infection.
Microperforation of gloves happens in around 18% cases at the end
of surgery and in 35% of cases after 2 hours of surgery. Although with
the double gloving technique, the risk of puncture is reduced to 4%, the
surgical handwash is an important step before wearing sterile gloves, further

emphasizing the strict quality control of water distribution system.4,20,21
Trained Personnel
Infection control team persons must be trained in SSI surveillance methods,
able to use knowledge of SSI and should be able to apply SSI definition in
different settings. Besides this, they must have basic computer skills and
be skilled and trained to provide feedback and education to healthcare
personnel when required.
Education Measures and Methods

Regular education should be provided to surgeons, anesthesiologists, and
perioperative personnel for implementation of recommended process
measures in order to minimize SSI.
Computer-aided Decision-making System and

Electronic Reminders
The application of this technology has been successful at several hospitals
in improving the rate of the timely administration of prophylactic antibiotic
in OR, although an increase of adverse drug reaction has been reported by
one study.22
Application of Electronic Data

Information technology infrastructure helps in appropriate compilation and
analysis of data so that process and outcome measures can be tracked and
required interventions can be implemented.
BEHAVIORAL MEASURES
Anesthesia Providers Practices
Various studies have reported contamination of anesthesia work area
by anesthesia provider practices; for example, use of multiple-dose
vials in more than one patient, airway management without the use of
gloves, nonperformance of hand hygiene (HH) after removing gloves,
use of anesthesia trolley drawers without performing HH. The Society for
Healthcare Epidemiology of America (SHEA) has provided recommendations
specific to the anesthesia work area to improve infection prevention
through HH, environmental disinfection, and implementation of effective
improvement efforts.1 Table 5 summarizes the SHEA guidance statement,
recommendations, and rationale behind each recommendation.
Table 5: Summary of Society for Healthcare Epidemiology of America (SHEA) expert guidance for infection prevention in anesthesia work area.1
Guidance statement Recommendation Rationale

1. When should At the minimum: •• If WHO 5 moments for HH is used as the standard, it
anesthesia providers •• Before aseptic tasks (e.g. inserting a central venous can be as high as 54/h which is logistically unfeasible
use hand hygiene catheter, drawing medication, piercing I/V bags). especially during induction.
(HH)? •• After removing gloves. •• Hand hygiene by anesthesia staff is increased with
•• When hands are soiled or contaminated. increased access to ABHR.37
•• Before touching the anesthesia cart.
•• When entering and exiting OR (even after removing
gloves).
•• Increase access to ABHR near anesthesia cart.
2. Use of double gloves Double gloves should be used during airway •• Anesthesia providers hand may become contaminated
during airway management and outer gloves are to be removed with upper airway secretions.
management. immediately after airway handling. •• Contamination of anesthesia work environment
Inner glove is to be removed as soon as possible and decreased after removal of the outer layer but was not
HH performed. completely eliminated38 and hence HH to be performed
after removal of the second layer.
3. What should be the Locate ABHR dispensers at the entrances to ORs and •• Facilitates use of ABHR for hand hygiene at the time of
location of ABHR near anesthesia providers inside OR. entry and exit from OR.
dispensers in the OR? •• ABHR dispenser location on the anesthesia machine has
shown increased compliance with HH.
4. Can ABHR be applied HH should be performed after changing gloves. •• Application of ABHR on gloves may interfere with the
on contaminated •• In case it is not feasible to perform HH then ABHR integrity of gloves.
gloves and further on gloves is better than no HH. •• In certain outbreaks of infection, CDC has
work performed with recommended use of ABHR multiple times on gloves.39
the same gloves on?
Contd…
Contd…

5. Should single-use •• Reusable laryngoscope handles and blades should •• Low-level disinfection does not remove blood and
laryngoscopes be used undergo high-level disinfection or sterilization. bacteria from laryngoscope handles.40
instead of reusable OR •• Reports have shown that contaminated laryngoscopes
ones? Use single-use laryngoscopes. have been responsible for the outbreak of infectious
•• After cleaning blades and handles should be packaged disease.41
until just prior to use.
•• Do not use handles that cannot undergo high-level
disinfection.
•• Same principles to be applied to supraglottic airway
masks.
6. Can covering of Data inadequate to make any such recommendations. ___
anesthesia machines
with disposable
covers prevent cross-
contamination?
7. How the cleaning and Clean and disinfect high-touch surfaces on the Various studies have demonstrated the contamination
disinfection of the anesthesia machine and anesthesia work environment of anesthesia machine and work area with potentially
anesthesia machine between OR uses (e.g. anesthesia machine work surface, pathogenic microbes which can be further transmitted
and work environment gas flow controls, vaporizer dials, adjustable pressure to patients through direct contact with contaminated
be done between two limiting (APL) valve, I/V stands, and fluid warmers). equipments, hands of anesthesia providers or contaminated
cases? •• All equipments which are in physical contact with medications. 23-25
patients should be cleaned thoroughly, e.g. pulse
oximeter, ECG leads and cable, reusable blood
pressure cuffs.
Contd…
Contd…

8. How should anesthesia •• Anesthesia providers should only use disinfected ports •• Peripheral intravenous tubing stopcocks and injection
providers use injection for intravenous access. ports used for medication administration frequently get
ports in OR? •• Scrub the port with a sterile alcohol-based contaminated.
disinfectant before each use immediately prior to each •• Reduction in central line-associated bloodstream
use or cover the ports continuously with isopropyl infections (CLABSI) by disinfecting catheter hubs,
alcohol-containing caps. needleless connectors, and injection ports43 have been
•• For rapid successions of injections as during reported.
induction of anesthesia, ports should be disinfected at
the beginning.
•• Compliance of disinfection of injection ports increases

with the use of sterile alcohol-containing caps.42
9. How should vials of Necks of ampules, medication vials, and rubber stoppers Caps of anesthesia medications are not sterile.
anesthesia drug be should be wiped with 70% alcohol before use.
disinfected at the time
of use?
10. What barrier All central venous catheters (CVCs) and axillary and Based on the compendium of strategies to prevent
precautions should femoral arterial lines should be inserted with full sterile bloodstream infections in Acute Care Hospitals43 and
be used at the time barrier precautions, i.e. mask, cap, sterile gown, sterile 2011 Healthcare Infection Control Practices Advisory
of insertion of gloves, and large sterile drape. Committee (HICPAC) guidelines.44
intravenous catheters? •• Place peripheral arterial lines (e.g. radial, brachial)
with a minimum of a cap, mask, sterile gloves, and a
small sterile perforated drape.
•• These measures are recommended even when
exchanging catheter over a guidewire.
Contd…
Contd…

11. When should Cap the needleless syringes used to administer multiple The risk of cross-contamination from the anesthesia
be recapping of doses of the drug in the same patient, after each use so provider’s hand and work environment will be reduced by
medication syringe that it covers the Luer connector on the syringe. capping of the syringe.
be done?
12. How should be •• Disinfect accessible outer surface of anesthesia supply Various studies have shown contamination of anesthesia
cross-contamination trolley between cases. workspace,27,45 anesthesia provider hands, BP cuff, pulse
of anesthesia trolley •• Always perform HH before opening anesthesia trolley oximeter probe, and have shown the cross-contamination
clean supplies be drawers. association with surgical site infection.26
prevented? •• As far as possible, anesthesia trolley’s top surface
should be free of supplies.
13. How long the Use provider prepared sterile injectable drugs as soon as •• Austin et al.47 found that contamination of the drugs
injectable drugs practically possible but may be used until the end of the prepared in the clinical setting is more than prepared in
prepared by the case in a setting of air less clean than ISO Class 5.46 a pharmaceutical setting.
anesthesia providers •• Studies have shown that propofol after preparation in
can be kept? syringes can expire within 6 hours.48
14. What is the time Minimal time duration should be there after piercing I/V ____
duration for which bags and their use. No specific time limit is identified.
I/V bags can be
pierced before
starting the use?
Contd…
Contd…

15. What is the protocol •• Use single-dose medication vials and flushes whenever Various guidelines for safe injection practices.49-51
for the reuse possible.
of syringes and In case of mandatory use of multiple-dose medicine
medication vials? vials, its use should be restricted to a single patient
only. New syringe and needle should be used for each
access.
•• Syringes and needles should not be used from one
patient to another.
16. When should the Cleaning and disinfection of monitor touch screen Studies have shown contamination with bacteria such
disinfection of touch and other surfaces in anesthesia workspace be done as coagulase-negative staphylococci, Bacillus spp., and
screens of monitors after each case and when there are obvious soiling and MRSA.45
in the anesthesia contamination.
work environment be
done?
17. What infection •• Guidelines as per hospital infection control policy •• Contaminated hands of anesthesia providers have
prevention measures should be followed for such patients in OR, e.g. been implicated in cross-contamination of anesthesia
should be taken for performing hand hygiene and use of personal workspace, e.g. anesthesia machine, anesthesia trolley,
patients in contact protective equipment (PPE). I/V stopcocks etc.23,26,52,53
isolation? •• Do environmental disinfection in-between cases, •• Routine cleaning does not decontaminate anesthesia
irrespective of patient’s multidrug-resistant organism workspace which is responsible for maximum cross-
status. contamination between cases.26
•• Maximum risk of contamination of anesthesia
workspace occurs during induction and emergence of
anesthesia.26,52
Contd…
Contd…

18. What measures can •• Infection prevention practices should be regularly •• Monitoring, evaluation, and feedback to providers are
bring improvement monitored and evaluated. important. Audit and feedback programs based on
in infection •• Management and physician leaders should: theory and evidence are effective.54
prevention practices –– Facilitate the use of process measures to improve •• Reminder cards and checklists have improved adherence
by anesthesia performance. to transmission-based precautions.55,56
providers? –– Share data which is real. •• Literature shows improvement with leadership
involvement.
19. What is the effect of Feedback on hand hygiene performance by the •• Institutions have used various types of monitoring and
feedback about data anesthesia providers should be given to bring overall feedback to increase providers’ compliance to HH.
on hand hygiene? improvement. •• Compliance with HH has improved with an intermittent
electronic reminder.
20. What is the effect •• Apply measures to assess the appropriateness and Various studies have shown the improvement in the
of providing adequacy of environmental disinfection and track the thoroughness of cleaning with different measures and
measurement and measures. feedback. One study has shown improvement in anesthesia
feedback data on •• Share the results with stakeholders for optimization of providers adherence following engagement by coaching.30
environmental adherence to recommended disinfection practices
disinfection?
(ABHR: alcohol-based hand rub; CDC: centers for disease control and prevention; ECG: electrocardiogram; MRSA: Methicilin–Resistant
Staphylococcus aureus; OR: operating room)
An extensive literature review has revealed that anesthesia workspace

can become contaminated with pathogens.23-26 The bacteria population
includes coagulase-negative Staphylococcus, Bacillus spp., Streptococcus, S.
aureus, Acinetobacter, and other gram-negative bacilli. The bacterial strains
which contaminate the anesthesia machine’s adjustable pressure-limiting
valve have been implicated more in cross-contamination of IV stopcock than
the bacterial strains which are found colonizing the patient’s nasopharynx
and axilla and on anesthesia providers’ hands.27 This contamination of I/V
stopcock was attributed to low hand hygiene by the anesthesia provider.
Cole et al.28 have demonstrated the bacterial growth in I/V stopcock where
even preservative containing propofol has been used for the case. Loftus
et al.29 in their study showed that after induction of anesthesia the bacterial
contamination of closed stopcock with alcohol disinfection was 0%, whereas
the same device with no disinfection before induction showed 4% bacterial
growth.
Various publications have emphasized the role of environmental cleaning
in reducing the bioburden of the anesthesia workspace and resultant cross
contamination.30-32 Gonzalez et al.33 in his study compared the commercial
disinfectant wipes with bleach and water and sodium hypochlorite. They
found that sodium hypochlorite was better than gauze and bleach and
water. They emphasized that bacteria should be physically removed from
anesthesia device surfaces when being used in different cases.
Anesthesia provider’s practice of airway management has also resulted
in bacterial contamination of laryngoscopes handles and blades and have
further resulted in cross-contamination of anesthesia workspace.34,35-37
“Double gloving” during airway management and sheathing of the
laryngoscope with the outer glove while it is being removed has resulted
in further reduction of contamination.35,36
As a future course of action Munoz et al.1 have suggested a need for
redesigning of anesthesia machine so that it can be effectively disinfected
in-between cases. They have also quoted examples where anesthesia trolley
is kept in the zone labeled as clean where only hands after hand hygiene
are allowed although this practice has been found to be challenging.
Staff Behavior
Airborne particles after coming in contact with walls, floor, skin or other
surfaces act as a vector for bacterial transmission. Foot traffic and opening
of doors generate air eddies which disperse these particles settled on an
unsterile floor. The role of minimizing OR staff movement in and out of OR
in decreasing surgical site infection rates in hospitals has been reported.57
Restricting the number of personnel in the OR to 5 or 6 ensures the airborne

bacterial count to up to 10 CFU/m3.58
Surgical Team Preparation

Noguchi et al.59 demonstrated the dispersion of particles in OR at the time of
unfolding of surgical drape by OR nurse at the time of preparing instrument
trolley, at the time of wearing of the gown and at the time of wearing and
removal of gloves. As mentioned above, airborne particles can act as a vector
for transmission of bacteria after coming in contact with unsterile areas.11
They recommended that OR staff should avoid above mentioned actions
near surgical site or sterile instruments. The timing of the preparation of
instrument trolley should be coordinated with the draping of the patient as
the rate of contamination increases with increase in the duration of opening
of instrument tray (4% after 30 minutes, 15% after 1 hour, and 30% after 4
hours).11 The containers and instruments must remain covered until the
time of starting of operation.
CLINICAL MEASURES
The literature search revealed various publications which have mentioned
clinical preventive measures for surgical site infection in the OR.7,8,11,13,14,60
WHO has provided evidence-based global recommendations for pre-,
intra- and postoperative period interventions.61 The guidelines have been
developed considering the source availability, values, and preferences.
Table 6 summarizes the interventions to be carried out in OR for
prevention of SSI as per WHO global guidelines along with the strength of
recommendation and quality of evidence.
Besides the above measures, redosing of prophylactic antibiotics have
been recommended in case of long procedures and in the case with excessive
blood loss during the surgical procedures.7,8,62 Redosing has to be done at an
interval of 2 half-lives (measured from the time the preoperative dose was
administered) and for every 1,500 mL estimated blood loss. Studies have
shown a lower rate of surgical site infection and death with use of surgical
safety checklist in OR.63-65
DISINFECTION AND STERILIZATION MEASURES

Proper biomedical waste (BMW) handling, disinfection, and sterilization
techniques of OR, surgical instruments, anesthesia equipments, and devices
play a significant role in infection prevention and reduction in associated
healthcare-acquired infections/SSI.
Table 6: Summary points for clinical intervention in the operating room (OR) to prevent SSI as per WHO Guidelines, 2018.61
Quality of
Topic Research questions Recommendations Strength evidence
1. Optimal timing for How does the timing of SAP •• The panel recommends that SAP should be Strong Low
preoperative SAP administration impact on the risk administered prior to the surgical incision when
of SSI and what is the precise indicated (depending on the type of operation).
optimal timing? •• The panel recommends the administration of Strong Moderate
SAP within 120 minutes before the incision while
considering the half-life of the antibiotic.
2. Surgical site Should alcohol-based antiseptic The panel recommends alcohol-based antiseptic Strong Low to
preparation solutions or aqueous solutions solutions-based CHG for surgical site skin preparation moderate
be used for skin preparation in patients undergoing surgical procedures.

in surgical patients and, more
specifically, should CHG or
PVP-I solutions be used?
3. Perioperative How safe and effective is the The panel suggests that adult patients undergoing Conditional Moderate
oxygenation perioperative use of an increased general anesthesia with tracheal intubation for
fraction of inspired oxygen in surgical procedures should receive an 80% fraction
reducing the risk of SSI? of inspired oxygen intraoperatively and, if feasible, in
the immediate postoperative period for 2–6 hours to
reduce the risk of SSI.
4. Maintaining Should systemic body warming The panel suggests the use of warming devices in the Conditional Moderate
normal body versus no warming be used for operating room and during the surgical procedure
temperature the prevention of SSI in surgical for the patient body warming with the purpose of
(normothermia) patients? reducing SSI.
Contd…
Contd…
Topic Research questions Recommendations Strength Quality of

Evidence
5. Use of protocols •• Do protocols aiming to The panel suggests the use of protocols for intensive Conditional Low
for intensive maintain optimal perioperative perioperative blood glucose control for both diabetic
perioperative blood glucose levels reduce the and nondiabetic adult patients undergoing surgical
blood glucose risk of SSI? procedures to reduce the risk of SSI.
control •• What are the optimal The panel decided not to formulate a recommendation
perioperative glucose target on this topic due to the lack of evidence to answer
levels in diabetic and question 2.
nondiabetic patients?
6. Maintenance Does the use of specific fluid The panel suggests the use of goal-directed fluid Conditional Low
of adequate management strategies during therapy intraoperatively to reduce the risk of SSI.
circulating surgery affect the incidence of
volume control/ SSI?
normovolemia
7. Wound protector Does the use of wound protector The panel suggests considering the use of wound Conditional Very low
devices devices reduce the rate of SSI in protector devices in clean-contaminated, contaminated
open abdominal surgery? and dirty abdominal surgical procedures for the
purpose of reducing the rate of SSI.
8. Incisional wound Does intraoperative wound The panel considered that there is insufficient evidence NA NA
irrigation irrigation reduce the risk of SSI? to recommend for or against saline irrigation of
incisional wounds before closure for the purpose of
preventing SSI.
Contd…
Contd…
Topic Research questions Recommendations Strength Quality of
Evidence
The panel suggests considering the use of irrigation of Conditional Low
the incisional wound with an aqueous PVP-I solution
before closure for the purpose of preventing SSI,
particularly in clean and clean-contaminated wounds.
The panel suggests that antibiotic incisional wound Conditional Low

irrigation should not be used for the purpose of
preventing SSI.
9. Prophylactic Does prophylactic negative The panel suggests the use of prophylactic negative Conditional Low
negative pressure pressure wound therapy reduce pressure wound therapy in adult patients on primarily
wound therapy the rate of SSI compared to the closed surgical incisions in high-risk wounds for
use of conventional dressings? the purpose of the prevention of SSI, while taking
resources into account.
10. Changing At the time of wound closure, is The panel decided not to formulate a recommendation NA NA
of surgical there a difference in SSI when on this topic due to the lack of evidence.
instruments instruments are changed for
fascial, subcutaneous, and skin
closure using a new set of sterile
instruments?
11. Antimicrobial- Are antimicrobial-coated sutures The panel suggests the use of triclosan-coated Conditional Moderate
coated sutures effective to prevent SSI? If yes, sutures for the purpose of reducing the risk of SSI,
when and how should they be independent of the type of surgery.
used?
Under open licence: CC BY-NC-SA 3.0 IGO.
(CHG: chlorhexidine gluconate; PVP-I: povidone-iodine; SAP: surgical antibiotic prophylaxis; SSI: surgical site infection)
Operating Room
Biomedical Waste Management
Appropriate segregation, transportation, and treatment of BMW as per local
and national guidelines are recommended.
Cleaning
Routine cleaning of OR removes contaminants, dust, and organic matter.
The floor is to be kept clean and dry which cause the natural death of
bacteria except for spores. Detergent decrease bacterial flora by 80% and
disinfection further reduces it to 95%. Wet mops instead of brooms are to
be used. Walls should be washed weekly with water, soap, and disinfectants.
Disinfection
Daily mopping of floors and walls with a disinfectant is to be done in the
morning before starting the procedures and at the end of the daily scheduled
cases. In between the operative procedures, the floor is to be mopped with
disinfectant.
Surgical Instruments
Associations of Perioperative Registered Nurses (AORN) have recommended
practices for cleaning and sterilization of surgical instruments.66 Preliminary
cleaning is done and all instruments are initially rinsed with water followed
by ultrasonic cleaning with disinfectant. Mechanic scrubbing is done with
soft bristle brush followed by air drying of instruments with high flow jet air
gun. After drying, packing of instruments done which are finally sterilized as
per protocol either by steam sterilization, ethylene oxide (ETO) sterilization
or plasma sterilization.
Anesthesia Equipment and Devices

Western world trend toward the use of disposable or single-use equipment
poses a problem in countries with limited resources. In case of reuse
of equipments or devices, decontamination is done before disinfection
or sterilization which reduces the bioburden. Further, disinfection and
sterilization are followed as per national/international guidelines set as
a protocol in association with hospital infection control policy. Various
methods are; chemical disinfection, autoclaving, ETO sterilization/
plasma sterilization which are used as per identification of type of items
(critical, semicritical, or noncritical) and required level of disinfection
(high, intermediate, or low-level disinfection) and sterilization.67 Necessary
personal protective equipment (PPE) should be used by personnel involved

in cleaning equipment as a protective measure to prevent injuries and
infection.68
SURVEILLANCE PROTOCOL
Microbiological surveillance of OR is done as monitoring for infection
prevention and is done based on the amount of surgical load, the occurrence
of SSI, availability of resources, funds, access to microbiologist, and the
maintenance of air quality in OR.5 Sampling involves:
• Air sampling
• Particulate counts
• HEPA filter efficiency test
• Swabs from anesthesia work area:
▪▪ Adjustable pressure limiting (APL) valve
▪▪ Vaporizer dials
▪▪ Gas flow controls.
• Culture of in use disinfection solution, e.g. from the disinfectant solution
used for endoscope cleaning and for disinfecting the reusable item.
• OR staff: nasal swabs, hand culture.
CONCLUSION
Infection prevention in the OR is a multidisciplinary approach. Flowchart 1
depicts the strategical measures to be taken to prevent infection at the level of
the OR staff, anesthesiologist and surgeons with collaborative support from
the infection control team and senior leaders of any healthcare organization.
An efficient HVAC system, preventing contamination of anesthesia work
area, appropriate and timely surgical antibiotic prophylaxis, disinfection
and sterilization of OR, surgical instruments, anesthesia equipments and
devices, microbiological surveillance protocol of OR play a significant role
in reducing cross-contamination in the OR and a further reduction in health
care-associated and surgical site infection.
KEY POINTS
• Efficient HVAC system to control temperature, humidity, pressure gradient,
microbial, and air particle contamination is to be installed at the time of
designing of OR as an infection prevention measure.
• Effective LAF use requires the restriction of personnel in OR, minimal
door openings, no change of gloves over surgical site or instrument tray,
avoidance of obstruction of vertical airflow by surgeon’s heads minimal
physical actions near the surgical fields and instruments.
Flowchart 1: Strategical measures to prevent infection in the operating room.
(AWA: anesthesia work area; BMW: biomedical waste; HH: hand hygiene; HEPA: high-efficiency particulate air; HVAC: heating, ventilation, and air
conditioning; OR: operating room)

• Frequent HH is recommended to reduce cross-contamination from the

anesthesia provider’s hands.
• Disinfection of anesthesia work environment is mandatory in between two
cases and at the end of all cases to reduce the intraoperative bacterial
transmission and for further reduction in surgical site infection.
• Safe injection practices are to be followed at all times by the anesthesia
providers and other staff in OR as per WHO guidelines.
• Taking precautions at the time of preparation of trolleys, draping of the
patient, and while changing gloves helps to minimize dispersion of airborne
particles.
• Appropriate time, type and dose of prophylactic surgical antibiotic,
surgical site preparation, use of increased concentration of perioperative
oxygenation, maintenance of normothermia, normovolemia, blood sugar
control, use of wound protection device, use of triclosan-coated sutures
are the elements for infection prevention in the OR.
• Cleaning and disinfection of OR floors and walls are equally important as
the appropriate segregation, transportation, and treatment of BMW.
• Surgical instruments, anesthesia equipment, and devices should be
disinfected and sterilized with utmost care to prevent any breach in sterility.
• Surveillance protocols in OR, monitoring, evaluation, feedback to
stakeholders, teaching and training with the involvement of infection
control team, OR staff, clinicians in OR and senior leaders impact infection
prevention in the OR.
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Regional Blocks for Shoulder Surgery: Sparing the Phrenic Nerve 353
CHAPTER
23 Regional Blocks for Shoulder

Surgery: Sparing the Phrenic
Nerve
Roberto C Blanco, Kumar G Belani
INTRODUCTION
Current standard care for any surgery include strategies that provide an
acceptable margin of safety, patient satisfaction, a reduction in time spent
in the medical facility, minimal or absent unwanted effects with built-in
economic efficiencies. For successful implementation of these strategies,
pain control plays a pivotal role. Patients with appropriate pain control have
fewer side effects, reduced length of stay and complications. Better pain
control is one of the indices of patient satisfaction.
During the last two decades, the practice of medicine has changed
substantially. Access to the internet has allowed physicians around the globe
to communicate efforts and share knowledge, translating to a faster pace and
development of strategies for patient care. At the same time, the evolution
of technology, particularly the application of ultrasound, has allowed for a
radical change in the way we perform bedside procedures in our patients.
In anesthesia, one of the specific applications of this technology has been
in the field of regional anesthesia. More importantly, ultrasound has opened
the door for clinicians seeking alternative therapies for patients, e.g. being
able to do the traditional nerve blocks with reasonable success.
The performance of traditional nerve blocks, like the interscalene block
(ISB), has evolved from anatomical landmarks through nerve stimulation,
to ultrasound-based techniques that have improved the quality, reliability,
and standardization of this block, with a decreased rate of occurrence of
local anesthetic toxicity.1
Interscalene block has become increasingly popular and its use has
risen during the last decade. This regional technique permits patients going
through moderate to severe shoulder painful procedures to recover faster
and return home after surgery with a lower incidence of readmission and
complications. Despite this, practitioners are challenged with its routine
application in patients with reduced pulmonary reserve, as most of the time
the ipsilateral phrenic nerve (PN) gets blocked during this procedure.
Several strategies are available to avoid the paralysis of the PN during
shoulder regional anesthesia. Decreasing the volume, slowing the speed of
injection, and moving the insertion point distal in the plexus, have been
attempted to reduce this risk. However, none of these strategies guarantee
the PN is always going to be spared.
A more definitive approach is possible and requires a review of
anatomy, particularly innervation of the joints and structures that are part
of the shoulder, and demonstrated during cadaveric studies and dissections
looking specifically into those terminal branches covering selected areas of
the shoulder joint area. This, along with the availability of ultrasound has let
us develop blocks that mitigate the pain of shoulder surgery while avoiding
PN paralysis.
ANATOMICAL CONSIDERATIONS
The nerves innervating the shoulder most consistently are the suprascapular
nerve (SSN), axillary nerve (AN), nerves to subscapularis (NS), with the
occasional contribution of the lateral pectoral nerve (LPN) and brachial
plexus posterior cord (PC) (Fig. 1).
The two main joints around the shoulder are the glenohumeral joint
(GHJ) and the acromioclavicular joint (ACJ).
In a recent study, Tran et al.2 detailed the innervation of the GHJ and
ACJs. To better understand the innervation of the GHJ, they divided this
joint into four quadrants (Fig. 2). As indicated in the Figure 2, the GHJ
is innervated mainly by the SSN, AN, and NS. There is an occasional
contribution by the LPN and direct branches of the PC.
In the case of the ACJ, the innervation comes from the SSN and LPN
(Figs. 3A to C). The SSN branches off the upper trunk of the brachial plexus
early, traveling laterally to the shoulder, giving off its acromial branch just
before crossing the suprascapular notch (SN). This acromial branch provides
innervation to the ACJ. After crossing the notch, the SSN divides into medial
and lateral branches, with the medial branch providing coverage to the
Fig. 1: Branches of the brachial plexus branches involved in shoulder innervation.

Fig. 2: Innervation of quadrants of the glenohumeral joint capsule.

(AC: acromion process; AN: axillary nerve; CP: coracoid process; LPN: lateral pectoral
nerve; NS: nerves to subscapularis; PC: posterior cord; SSN: suprascapular nerve)
Source: With permission from BMJ Publishing Group Ltd.
supraspinatus muscle and the lateral branch innervates the posterosuperior

GHJ and infraspinatus muscle.
The AN leaves the PC of the brachial plexus behind the pectoralis minor
muscle, from where it takes an inferolateral direction. The main trunk of AN
provides 1–3 articular branches to the anteroinferior GHJ quadrant prior
to its bifurcation into the anterior and posterior divisions. These branches
travel with the anterior circumflex humeral artery and course laterally
between the tendons of the subscapularis and latissimus dorsi.
Coursing through the quadrilateral space the AN divides into an
anterior and posterior divisions. The posterior division, after emerging
from the quadrilateral space gives off 1–3 articular branches to the GHJ
posteroinferior capsule, while the anterior division occasionally gives off
2–3 articular branches that terminate in the transverse humeral ligament.
Besides the joint, the AN provides motor fibers to the infraspinatus and teres
minor muscles as well as sensory fibers to the skin.
The NS has two components, upper and lower, both branching from
the PC. The upper component travels along the superior border of the
subscapularis, providing 1–2 branches to the anterosuperior part of the GHJ.
Occasionally, this innervation is derived directly from the PC of the brachial
plexus.
Figs. 3A to C: Frequency map of innervation of GHJ and ACJ. Numbered arrows in A

to C indicate course of: (1) medial trunk of SSN; (2) motor branches of SSN supplying
infraspinatus; (3) anterior and posterior divisions of AN.
(AC: acromion process; ACJ: acromioclavicular joint; AN: axillary nerve; BG: bicipital
groove; br: branch; CL: clavicle; PC: posterior cord; div: division; GHJ: glenohumeral
joint; HH: humeral head; ISF: infraspinous fossa; LPN: lateral pectoral nerve; SBF:
subscapular fossa; SGN: spinoglenoid notch; SN: suprascapular notch; SS: spine of
scapula; SSF: supraspinous fossa; SSN: suprascapular nerve; *: coracoid process)
Source: With permission from BMJ Publishing Group Ltd.
The LPN derived from the lateral cord of the brachial plexus runs in the
deltopectoral triangle. After traveling within the neurovascular bundle with
the acromial branch of the thoracoacromial artery, it usually provides 1–2
articular branches to innervate the ACJ, and occasionally sends a branch to
the GHJ superoanterior or inferoanterior quadrants.
PRACTICAL IMPLICATIONS
For a proper approach to the surgical care of the patient requiring shoulder
surgery, we need to define the following:
• Patient comorbidities and suitability for general anesthesia
• Type of surgery
• Analgesic versus anesthetic block.
Even with pulmonary pathology precluding the use of the ISB, it is

important to confirm if the patient otherwise can tolerate the physiological
changes of general anesthesia. Many shoulder surgeries are done in the
sitting position and maintaining a proper perfusion pressure to the brain
is vital. With an asleep patient, we rely on electroencephalogram (EEG) or
brain near-infrared spectroscopy as surrogates of perfusion. However, in
some instances, mild sedation or a patient awake and responsive may be
necessary to evaluate cerebral function closely. With the latter patient in
mind, we need a block that provides comprehensive shoulder coverage.
In the awake or lightly sedated patient that is scheduled for shoulder
arthroplasty or extensive arthroscopic intervention [Superior labrum
anterior and posterior (SLAP) or dislocation], one needs to block the SSN3
(this is done at the level of the SN). (The subomohyoid approach carries
some risk as the local anesthetic may spread cephalad to the PN).4 One also
needs to block the brachial plexus, distal to the clavicle (costoclavicular5,6 or
infraclavicular approach7), and the supraclavicular nerves8 (at the emergence
of the cervical superficial plexus) so as to provide comprehensive anesthetic
coverage. During the superficial cervical block, the needle must remain
superficial to avoid puncture of the prevertebral fascia, with the potential
spreading of the local anesthetic to the PN.
In the same awake patient with a less extensive surgery (arthroscopy for
rotator cuff repair only for example), the SSN block, along with AN block (the
anterior approach9 can have better coverage than the inferior axilla,10 and
the quadrilateral space approaches11), and superficial cervical block conveys
an anesthetic block that is adequate. With this block combination, direct
branches of the posterior brachial plexus cord, SN, and LPN are not covered,
increasing the chance for needing intravenous (IV) supplementation or
sedation.
When the patient is going to receive general anesthesia, minimizing
the amount of general anesthesia can allow fast-tracking, improve patient
satisfaction, and reduce side effects. For some patients, the ability to feel
and move the distal part of the upper extremity may also be important in
patient satisfaction.
Because the patient is asleep, the amount of block options increases
and depends upon the expected desired result. As with the awake patient,
the combination LPN and brachial plexus block distal to the clavicle will
provide excellent analgesic coverage after most shoulder procedures. In this
case, coverage of the upper part of the shoulder skin with superficial cervical
block might not be necessary.
Aliste et al.12 demonstrated in their study that costoclavicular block
(CCB) alone versus ISB was not inferior for postoperative analgesia after
shoulder arthroscopic surgery. However, the authors did not quantify the
amount of general anesthesia used, which may be important in patients
with limited physiologic reserve.
If the patient expresses a desire to maintain the motor and sensory

function of the ipsilateral upper extremity, blocking the SSN and AN alone
will provide adequate analgesia to most of the GHJ and ACJ areas while
sparing the distal arm.
With the option to add block adjuncts (dexamethasone, clonidine, etc.) or
use liposomal bupivacaine (instead of or in addition to regular bupivacaine),
the duration of these blocks can be extended. This prolongation may reduce
the incidence of opioid-related adverse drug events, the likelihood of
chronic pain after surgery, and hospital length of stay.
SPECIFIC BLOCKS
The specific description of each block is beyond the scope of this review.
However, the reference to each one is attached, as well as the reasons why
the authors desire a preference for one approach over another.
Suprascapular Nerve Block

Suprascapular Fossa
The US approach was originally described by Harmon and Connor.3
Block at this level covers all the SSN innervation relevant to the shoulder
with no chance of local anesthetic spreading to the PN. Podgórski
et al.13 described a pseudo-SN that can make the identification of the
true notch challenging, making the use of nerve stimulator necessary in
some cases.
Subomohyoid
In a cadaveric study, 10 SSN blocks were done in five fresh cadavers. Sehmbi
et al.4 showed that despite the low volume used (5 mL), the PN was still
stained in 20% of the injections, making this approach less desirable when
sparing the PN is a priority.
Brachial Plexus Block

Costoclavicular
The costoclavicular space has been anatomically defined6 and the block
technique described by Karmakar et al.5 Although more literature is still
needed, the theoretical advantages of the CCB approach are the consistent
location and closer proximity of the brachial plexus cords, as well as easier
visualization in many patients. This makes the injection of the medication
and the coverage of the three cords more reliable. Caution should be used
with volume, speed, and pressure of injection as this location is almost
posterior to the clavicle and can have some risk of cephalad spreading.
Infraclavicular
When compared with the CCB block, traditional lateral fossa infraclavicular
block takes a little longer to set up.14,15 Either performed as a single or double
injection its quality is similar.16
The main caveat may be needle visualization, especially in obese
patients, due to the steep angle of approach. On the other hand, it is a
technique that more people are familiar with.
Retroclavicular
In the retroclavicular approach to the infraclavicular fossa, the needle is usually
parallel to the ultrasound beam and therefore the visualization, especially of the
needle tip, is typically better than with the infraclavicular approach.
One of the dogmas of ultrasound-guided blocks is to keep the needle,
and needle tip, under direct vision at all times, so the risk of trauma,
especially to neural structures, is minimized. During this approach, the
needle is advanced without a direct vision for the segment behind the
clavicle. Sancheti et al.17 showed in a study performed in three cadavers
that the SSN and vessels are not free of risk. Therefore, this block may not
be the safest approach to the brachial plexus below the clavicle.
Axillary Nerve
Anterior Approach
The novel approach described by Gonzalez-Arnay et al.9 in a cadaveric
study produces coverage of the subscapularis muscle fascial space in
the anterolateral part of the muscle, where the AN runs after leaving the
posterior trunk. As the nerve is reached, soon after leaving the plexus, this
approach is going to cover all the AN branches. This approach may be
difficult in a patient unable to extend and externally rotate the upper extremity.
Inferior Axilla
In this technique, recently described by Chang et al.10 the AN is directly
visualized in the long axis when it passes medial to the humeral head and
before emerging through the quadrilateral space. This approach covers
some branches missed during the quadrilateral approach. To be performed,
the patient must be able to abduct the upper extremity.
Posterior Approach (Quadrilateral Space)

Described by Rothe et al.11 this block is not difficult to perform. Unfortunately,
it may miss branches coming off the AN before its crossing through the
quadrilateral space. This may explain why the study by Dhir et al.14 showed
differences in quality of SSN and AN block combination versus ISB.
Supraclavicular Nerves
Described by Tran et al.16 the supraclavicular nerves can be blocked at
their emergence from the superficial cervical plexus. Again, always consider
staying superficial to avoid puncture of the prevertebral fascia with potential
direct spreading to the PN. The goal of this block is to anesthetize the skin
covering the supraclavicular area.
CONCLUSION
With our current knowledge of shoulder innervation, as well as the
availability of ultrasound, it is possible to provide complete shoulder
analgesia and anesthesia for patients with limited pulmonary reserve. This
is accomplished through careful and slow injection of limited volumes
of local anesthetic performed at both the level of the SSN and brachial
plexus below the clavicle. A more comprehensive block can be obtained
if the supraclavicular nerves are also blocked, covering the skin around
the supraclavicular area. The use of ultrasound, as well as nerve stimulator
and injection pressure monitoring, are optional tools to complement safety
when the anesthesiologist judges that they are necessary.
An important factor when deciding what type of block or block
combination is going to be used should weigh not only type of surgery,
patient reserve, and type of anesthesia, but also practitioners experience
and familiarity with the blocks being chosen.
The most comprehensive SSN block coverage is obtained when the
procedure is performed at the level of the SN. In the case of the AN block,
the anterior approach seems to render the best coverage for this nerve.
Finally, if the brachial plexus is going to be blocked, the decision between
costoclavicular versus lateral infraclavicular approach can be made based
on the quality of the US image obtained, favoring the one that provides a
clearer picture of the brachial plexus cords.
New information is becoming available constantly, and by the time this
paper will reach you, chances are, new data might be favoring one approach
over another, with even new options already available.
KEY POINTS
• The use of the traditional ISB for shoulder surgery is almost always
associated with blockade of the PN. Strategies of decreasing anesthetic
volume and concentration, or moving the approaching point caudally
above the clavicle, have proven to be not reliable in sparing the PN.
• Two important sources of pain after shoulder arthroplasty are the GHJ
and the ACJ.
• Suprascapular nerve, AN, NS, with the occasional contribution of the LPN
and brachial plexus PC encompass the innervation for the GHJ.
• The ACJ is innervated by the SSN and the LPN.
• Selective blocks of these contributing nerves make it possible to perform
shoulder surgery while avoiding paralysis of the diaphragm.
• The extent of block coverage by these nerves will be dictated by the type
and extent of surgery. Patient comorbidities, additional anesthetics, and
practitioner familiarity with the blocks described also play a role.
REFERENCES
1. Neal JM, Brull R, Horn J, et al. The Second American Society of Regional
Anesthesia and Pain Medicine evidence-based medicine assessment of
ultrasound-guided regional anesthesia: executive summary. Reg Anesth Pain
Med. 2016;41:181-94.
2. Tran J, Peng PWH, Agur AMR. Anatomical study of the innervation of
glenohumeral and acromioclavicular joint capsules: implications for image-
guided intervention. Reg Anesth Pain Med. 2019;44:452-8.
3. Harmon D, Conor H. Ultrasound-guided suprascapular nerve block technique.
Pain Physician. 2007;10(6):743-6.
4. Sehmbi H, Johnson M, Dhir S. Ultrasound-guided subomohyoid suprascapular
nerve block and phrenic nerve involvement: a cadaveric dye study. Reg Anesth
Pain Med. 2019;44:561-4.
5. Karmakar MK, Sala-Blanch X, Songthamwat B, et al. Benefits of the
costoclavicular space for ultrasound-guided infraclavicular brachial plexus
block: description of a costoclavicular approach. Reg Anesth Pain Med.
2015;40(3):287-8.
6. Sala-Blanch X, Reina MA, Pangthipampai P, et al. Anatomic Basis for Brachial
Plexus Block at the Costoclavicular Space: A Cadaver Anatomic Study. Reg
Anesth Pain Med. 2016;41(3):387-91.
7. Sandhu NS, Capan LM. Ultrasound-guided infraclavicular brachial plexus
block. Br J Anaesth. 2002;89:254-9.
8. Tran DQ, Dugani S, Finlayson RJ. A randomized comparison between
ultrasound-guided and landmark-based superficial cervical plexus block. Reg
Anesth Pain Med. 2010;35:539-43.
9. González-Arnay E, Jiménez-Sánchez L, García-Simón D, et al. Ultrasonography-
guided anterior approach for axillary nerve blockade: An anatomical study.
Clin Anat. 2019:23394.
10. Chang KV, Lin CP, Lin CS, et al. A novel approach for ultrasound guided axillary
nerve block: the inferior axilla technique. Med Ultrasonogr. 2017;19(4):457-61.
11. Rothe C, Asghar S, Andersen HL, et al. Ultrasound-guided block of the
axillary nerve: a volunteer study of a new method. Acta Anaesthesiol Scand.
2011;55(5):565-70.
12. Aliste J, Bravo D, Layera S, et al. Randomized comparison between interscalene
and costoclavicular blocks for arthroscopic shoulder surgery. Reg Anesth Pain
Med. 2019;44:472-7.
13. Podgórski M, Rusinek M, Cichosz M, et al “Pseudo-suprascapular notch”: is
it a sonographic trap in suprascapular nerve block? Reg Anesth Pain Med.
2019;44:77-80.
14. Dhir S, Sondekoppam RV, Sharma R, et al. A Comparison of Combined

Suprascapular and Axillary Nerve Blocks to Interscalene Nerve Block for
Analgesia in Arthroscopic Shoulder Surgery: An Equivalence Study. Reg Anesth
Pain Med. 2016;41(5):564-71.
15. Songthamwat B, Karmakar MK, Li JW, et al. Ultrasound-guided infraclavicular
brachial plexus block: prospective randomized comparison of the lateral
sagittal and costoclavicular approach. Reg Anesth Pain Med. 2018;43:825-31.
16. Tran DQ, Bertini P, Zaouter C, et al. A prospective, randomized comparison
between single- and double-injection ultrasound-guided infraclavicular
brachial plexus block. Reg Anesth Pain Med. 2010;35(1):16-21.
17. Sancheti SF, Uppal V, Sandeski R, et al. A Cadaver Study Investigating Structures
Encountered by the Needle During a Retroclavicular Approach to Infraclavicular
Brachial Plexus Block. Reg Anesth Pain Med. 2018;43(7):752-5.
Current Status of Methylene Blue in Anesthesia and Intensive Care 363
CHAPTER
24 Current Status of Methylene

Blue in Anesthesia and
Intensive Care
Devalina Goswami
INTRODUCTION
Methylene blue (MB) has the credit of being the first totally synthetic
compound used for medicinal purposes. The properties of MB have found
extensive use in medicine for a variety of purposes. Initial medical literature
mentions its use in the treatment of malaria.1 It’s color and staining properties
have been utilized in diagnostic procedures of gynecology, urology, and in
surgery of the parathyroid glands.
In anesthesia and intensive care as well, it has proved valuable in several
ways. It has been used extensively in the treatment of methemoglobinemia
(MHgb) and as an indicator/staining dye. Current interest in MB among
anesthesiologists and intensivists revolve mostly around its vasopressor
(noncatecholamine) properties, its ability to counteract and reverse many
of the effects of MHgb, ifosfamide toxicity, and hydrogen sulfite poisoning.
It is also used as a dye in regional blocks to delineate tissue planes and
anatomical structures.
HISTORICAL BACKGROUND
Methylene blue is an aniline dye derivative, first synthesized by Heinrich
Caro in 1876 for the textile industry. Robert Koch used it for staining
tuberculosis bacilli. Later in 1891, Ehrlich and Guttman applied it in the
treatment of malaria.2
PHYSIOCHEMICAL PROPERTIES
Methylene blue is chemically known as methylthioninium chloride and
is represented by the formula C16H18CIN3S. It is a heterocyclic aromatic
molecule, available as an odorless dark green powder that yields a blue color
on dissolving in water.3,4 Nicotinamide adenine dinucleotide phosphate
(NADPH) metabolizes MB to leukomethylene blue (LMB), which is excreted
primarily in the urine, giving it a bluish-green color. A small portion of the
MB gets excreted unchanged in the urine. MB has a terminal half-life (t½)
of 5.25 hours.5
MECHANISM OF ACTION
In Methemoglobinemia
Red blood cells carry O2 in very high concentrations; as a result, they are
exposed to O2 free radicals, which results in formation of methemoglobin.
Methemoglobin is produced by the process of oxidation of iron from the
ferrous (Fe2+) to the ferric (Fe3+) form in the normal hemoglobin molecule.
The ensuing structural change of the hemoglobin molecule renders
it incapable of binding and subsequently delivering oxygen to tissues
resulting in hypoxemia. This change of hemoglobin structure causes the
oxygen dissociation curve to be shifted to the left. Normal methemoglobin
concentration in the blood is ≤1%.6 The levels of methemoglobin are
maintained at a normal physiological level by several endogenous reduction
systems. The predominant system responsible for 99% of methemoglo -
bin reduction is the cytochrome-b-5 reduction system. NADPH methemo
globin reductase usually contributes negligible amount of methemoglobin
reduction under normal circumstances. However, it has a special affinity
for exogenous dyes like MB. MB is reduced by NADPH methemoglobin
reductase in the body to LMB, which in turn reduces methemoglobin to
hemoglobin.7,8
Nicotinamide adenine dinucleotide phosphate methemoglobin
reductase pathway is deficient in patients with G6PD deficiency leading to
high levels of MB, which could, in turn, lead to more oxidative stress and
more oxidation of methemoglobin. Therefore, treatment of severe acute
MHgb by MB is contraindicated in G6PD deficiency.7
As a Vasopressor
In states of shock, MB serves its action as a vasopressor by increasing
peripheral vascular resistance and reversing the myocardial depression.
This action is mediated through inhibition of soluble guanylyl cyclase (sGC)
and nitric oxide synthase (NOS) activity.9,10 NOS produce nitric oxide (NO)
via two subsets of NOS. One is the constitutive NOS (cNOS) that remain
constantly active and the second is the inducible NOS (iNOS), which gets
activated in the presence of cytokines and endotoxins produced during
inflammation or sepsis. iNOS is present in cardiac myocytes and vascular
smooth muscle cells.2 NO activates sGC, which in turn produces cyclic
guanosine monophosphate (cGMP). As the concentration of cGMP increases,
relaxation of the vascular smooth muscle cells and the myocardium occurs.
In addition, an elevated level of cGMP increases the vascular permeability.2
Methylene blue binds to the iron heme moiety of sGC, which prevents
an increase in the levels of cGMP. MB also has direct inhibitory effect on
the NOS. MB competitively blocks the target enzymes of NO production
thereby reducing the responsiveness of vessels to cGMP thus restoring the

vascular tone.3
EFFECT OF METHYLENE BLUE ON ANESTHETICS

Literature describing the effect of MB on anesthetics in humans are few and
with inconclusive evidence. A randomized controlled trial studied the effects
of MB on the requirement of propofol during induction and maintenance of
anesthesia of parathyroid surgery. It was observed that patients pretreated
with MB had 50% reduced propofol requirements both during induction
and maintenance of anesthesia along with delayed emergence.11
The potential target in the brain for the action of the anesthetic agents
like propofol is considered to be the glutamate-NO-cGMP pathway.
Evidence from animal studies shows MB causing interference with the
effects of anesthetic agents within the brain by inhibiting both the NOS
and guanylate cyclase (GC) activity.12
It has been speculated that MB-induced blockade of the NO-cGMP
could result in a smaller volume of distribution and a lower elimination
clearance owing to a reduced hepatic blood flow, eventually contributing
to increased propofol plasma and effect-site concentrations.12
Experiments in animals where MB was administered in the ventricles
have demonstrated a decrease in the minimum alveolar anesthetic concen
tration (MAC) of volatile anesthetic agents.13
Pre-emptive MB infusion in a dose of 2 mg/kg over 20 minutes before
induction of anesthesia in hemodynamically stable patients of perforation
peritonitis have shown more stable postinduction hemodynamics as
compared to patients who received normal saline.14
A case report has described prophylactic administration of preoperative
MB in a patient with congenital methemoglobinemia. There was a significant
decrease in the methemoglobin levels and increase in the fractional oxygen
saturation from a preoperative value of 80.7–94.7% within 5 minutes of MB
administration and 97.7% after 2 hours. This had improved the safety margin
against perioperative hypoxemia.15
Transient interference of pulse oximetry readings is seen with MB.
However, extreme vigilance is mandatory while interpreting the pulse
oximetry readings, as MB is known to cause pulmonary edema.16 A case
report has described dramatic reduction in the bispectral index while using
MB infusion for the treatment of dapsone-induced MHgb.17 Whether MB
has any significant effect on anesthetics or not will only be known from
future research.
TREATMENT OF METHEMOGLOBINEMIA
The only Food and Drug Administration (FDA) approved indication for the
use of MB is in pediatric and adult acquired MHgb.
The first step in the treatment of MHgb is aimed at removing the

causative agent. If MHgb is symptomatic, which usually occurs with MHgb
levels >15%, administration of MB as 1–2 mg/kg over 5 minutes should be
attempted. If cyanosis persists, a second dose of MB may be given. Exchange
transfusion or hyperbaric oxygen may be beneficial if treatment with MB
fails to alleviate the symptoms.8
It is a paradox, however, that MB can cause MHgb as well. It has been
suggested that MB can act as an oxidizing or reducing agent in different
clinical situations. In contrast to the ability of MB to reduce methemoglobin
to Hgb, through enzymatic reduction pathways, MB also has the capacity
to oxidize Hgb to methemoglobin. In normal circumstances, MB favors the
reduction of methemoglobin to Hgb unless large doses of MB are administered
or if MB is administered too quickly. A local high concentration of the drug
results in methemoglobin formation.8 Worsening of undiagnosed congenital
MHgb was seen after treatment with MB.18
VASODILATORY SHOCK
Fluid replacement and catecholamines remain the first line of treatment in
vasodilatory shock. Catecholamines are often implicated in the causation of
arrhythmias and increased myocardial oxygen demand. Prolonged treatment
with high dose catecholamines leads to downregulation and desensitization
of adrenergic receptors. The focus has now shifted to noncatecholamine
vasopressor like vasopressin, terlipressin, and MB.19 Meta-analysis of MB in
vasoplegic shock reveals it to be effective in increasing blood pressure and
systemic vascular resistance (SVR) without having any detrimental effect
on survival.20
CARDIAC SURGERY AND VASOPLEGIA

Methylene blue has found itself a place as a noncatecholamine vasopressor
in the treatment of vasoplegia unresponsive to fluid and catecholamine
therapy. The term vasoplegia is used to describe a distributive shock-like
status caused by excessive loss of vascular tone.21
Vasoplegic syndrome (VS) is a common complication following major
cardiovascular surgery. It has been reported to occur in 5–25% of patients
during or after cardiopulmonary bypass (CPB).3,22 The incidence of VS may
be as high as 30–50% if there are associated predisposing factors.23
Gomes et al. were the first to describe VS in 1994. It is a clinical condition
defined by the presence of all of the following criteria:
• A mean arterial pressure (MAP) < 50 mm Hg
• Cardiac index > 2.5/L/m2
• Right atrial pressure < 5 mm Hg
• Left atrial pressure < 10 mm Hg, and

• Low SVR (<800 dynes/cm5) in the absence of obvious infection and
despite high doses of intravenous (IV) norepinephrine infusion
(>0.5 µg/kg/min).24
The mechanism leading to the development of VS is largely unknown.
The etiology is postulated to be multifactorial. Hemodilution, baroreceptor
reflexes, complement activation, and endogenous compounds like NO,
carbon monoxide, and oxygen-free radicals have been implicated for
causing vasodilation.23
Vasoplegic syndrome is associated with a systemic inflammatory
response that results in endothelial cell dysfunction and formation of NO
from L-arginine in response to the enzyme iNOS. The newly formed NO
escalates the production of cGMP which is responsible for vasoplegia.
Excessive formation of NO and cGMP is related to profound vasodilatation,
myocardial depression, and decreased response to catecholamines.21
Methylene blue is often administered as a rescue agent for treating
post-CPB vasoplegia. It directly competes with NO for activation of GC.
Furthermore, MB inhibits iNOS, potentially reducing the escalation of
NO concentration that occurs with CPB and other physiologic stress. MB
thus prevents NO-mediated dephosphorylation of myosin and the ensuing
vasodilation.21
Methylene blue has been reported to be successful in treating VS arising
out of a variety of situations in cardiac surgery. Successful treatment of VS
arising after tricuspid valve repair of a patient of carcinoid syndrome has
been reported with the use of MB.25 MB has been used to reverse reactionary
vasoplegia occurring after protamine sulfate administration in a patient
undergoing coronary artery bypass grafting.26
Case report on the successful use of MB in pediatric patient who
developed VS following cardiac transplant is described in the literature. MB
was used in a dose of 1 mg/kg in the catecholamine unresponsive 5-year-old
patient. Significant improvement was seen with an increase in the MAP and
subsequent tapering off of the vasopressor support.27
The authors, however, suggest that MB should be considered as a rescue
vasopressor for pediatric patients only when the conventional therapy fails.
Furthermore, they have noted that dosing regimens and protocols for the
use of MB in the treatment of catecholamine resistant VS are poorly defined
in the pediatric patients.
The most commonly used dosage in cardiac surgery is reported to
be 2 mg/kg intravenous bolus, followed by a continuous infusion of
2 mg/kg/h.28 Early administration of MB after cardiac surgery was seen to
be associated with reduced renal failure and perioperative mortality versus
late administration.29 It has been postulated that MB works best in the first
8 hours of shock where there is upregulation of NOS and sGC activity. The
next 8 hours see a downregulation of NOS and sGC followed by upregulation

in the third 8 hours. But effectiveness of MB decreases in the third 8 hours,
as there are metabolic acidosis and circulatory failure in states of prolonged
shock.28
SEPSIS
The mechanism of action in septic shock is also mediated via inhibition of
NOS and sGC which are responsible for the increased intracellular cGMP
concentration which eventually leads to relaxation of vascular smooth
muscles and myocardium, and also increased vascular permeability.
Methylene blue administration in patients of septic shock results in an
increase in the MAP and decrease in the requirements of catecholamines.
However, conclusive effects of MB on morbidity and mortality in patients of
septic shock still remain unknown due to lack of well-designed prospective
studies.10,19
ANAPHYLACTIC SHOCK
Anaphylactic reactions occur due to antigen and antibody [Immunoglobulin
E (IgE) produced from previous exposure] reaction leading to degranulation
of mast cells along with release of chemical mediators like prostaglandins,
leukotrienes, and histamine. Among these chemicals, histamine is implicated
in causing the profound effects of anaphylaxis. Endothelial NOS activity is
upregulated by histamine leading to NO production, which in turn activates
GC with a consequent increase in cGMP.
The role of MB in anaphylactic shock has been described in literature.
The proposed mechanism of action of MB in anaphylactic shock is through
blocking GC activity. Inhibition of GC interrupts excessive activation of
NO-cGMP pathway resulting in reversal of the vasodilatation mediated via
histamine.2
Severe anaphylaxis has been reported from exposure to latex in surgeon’s
gloves, in a patient with history of previous three surgeries. IgE typically
mediates a latex anaphylactic reaction. MB was used when conventional
therapy with high doses of catecholamines was ineffective. Administration
of MB was associated with concomitant improvement in hemodynamics
and tissue perfusion. Based on several studies, the authors have mentioned
the following dosing patterns in shock:10
• Vasodilatory shock: A therapeutic bolus of 1–2 mg/kg over 10–20
minutes. As the terminal half-life of IV administration of MB is
5–6 hours, a continuous infusion for 2–3 days may be beneficial.
• Septic shock: IV bolus of 2 mg/kg followed by continuous infusion of
0.25 mg/kg/h for up to 6 hours.
Bolus doses in the range of 1–3 mg/kg have shown favorable hemo
dynamic profiles without deleterious effects on splanchnic perfusion, but
higher doses (7 mg/kg) have shown to decrease splanchnic perfusion.
Continuous infusion rates of 1 mg/kg/h have shown favorable hemo
dynamic augmentation without compromising splanchnic perfusion.
The most suitable time for administration of MB has been studied. It has
been observed that MB is more effective when administered early at a time
when MAP is still higher.30
ORTHOTOPIC LIVER TRANSPLANTATION

The use of MB has been extended to the treatment of hypovolemic shock
and ischemia-reperfusion injury following orthotopic liver transplantation
(OLT). A randomized controlled trial to study the preventive effect of MB
on hypotension upon vascular clamp release following OLT was studied
on 36 patients. The group receiving MB as a bolus of 1.5 mg/kg just before
graft reperfusion had significantly increased MAP, reduced epinephrine
dosages, higher cardiac indices, and reduced serum lactate levels at
1 hour after administration, compared with the control group who received
normal saline bolus.31 In contrast, in a retrospective study where MB was
administered just prior to reperfusion at a dose of 1–1.5 mg/kg neither
did prevent postreperfusion hypotension nor did decrease vasopressor
requirements.32
However, recent case reports give a favorable picture of MB in OLT as
it has shown to improve hemodynamics when used as a rescue drug in
refractory hypotension after hepatic reperfusion during transplantation. A
recent review article on the use of MB in intraoperative vasoplegia opines
that routine use during liver transplantation cannot be supported at this
time because of the paucity of data.10
CARDIOVASCULAR DRUG POISONING

A case report describes the use of MB to treat refractory distributive shock
caused by cardiovascular drug overdose with amlodipine. Dihydropyridine
calcium channel blockers causes phosphorylation of endothelial NOS
resulting in increased NO production. MB blocks the pathway resulting in
the reversal of the symptoms.33
IFOSFAMIDE TOXICITY
Ifosfamide-induced encephalopathy (IIE) occurs in about 10–40% of
patients receiving high doses of the drug. The clinical spectrum ranges from
mild somnolence, agitation, confusion, and hallucinations to deep coma.
Its occurrence is reported to be more common with oral intake than IV

administration.34
Ifosfamide is an alkylating agent and oxazaphosphorine antineoplastic
agent (a nitrogen mustard derivative). It is a prodrug dependent on hepatic
activation to its cytotoxic metabolite ifosfamide mustard. Cytochrome p450
metabolizes ifosfamide mustard to generate the active alkylating agents,
4-hydroxy-ifosfamide and isophosphoramide mustard. Both ifosfamide
and its metabolites are capable of crossing the blood–brain barrier (BBB)
to cause IIE.35,36
The metabolites can inhibit the electron-binding flavoproteins in
the mitochondrial respiratory chain. The inhibition of the mitochondrial
respiratory chain may also lead the accumulation of reduced form of
nicotinamide adenine dinucleotide (NADH). This, in turn, prevents
the dehydrogenation of aldehydes, such as the ifosfamide metabolite
chloroacetaldehyde (CAA) a potential neurotoxic substance, which needs
NAD for their oxidation.34,36
Methylene blue has been found to counteract some of these metabolic
pathways by acting as an alternative electron acceptor, replacing the inhibited
flavoproteins thereby restoring the mitochondrial respiratory chain function.
It also has the capacity to oxidate NADH, allowing dehydrogenation of the
aldehydes. A preventive action of MB in the causation of IIE is assumed to
be due to inhibition of the plasma and extrahepatic monoamine oxidases.34
The recommended IV dose of MB for treatment of IIE is 50 mg every 4
hours and the dose for secondary prophylaxis of IIE is 50 mg every 6 hours,
either intravenously or orally.35
HYDROGEN SULFITE TOXICITY

Hydrogen sulfide (H2S) is a chemical product with significant hazards in
the gas and farming industry. It is used for suicidal purposes as well as it is
easily producible and causes rapid death when taken in high doses. Death
due to H2S poisoning is secondary to a pulseless electrical activity (PEA).
Long-term cognitive or motor deficits develop due to direct toxicity of H2S
on neurons combined with the consequences of a prolonged apnea and
circulatory failure.
The toxicity of H2S is partly attributed to the inhibition of mitochondrial
cytochrome c oxidase thus preventing adenosine triphosphate (ATP)
formation and promoting the production of reactive oxygen species (ROS).
H2S is also thought to affect cysteine residues of numerous proteins by direct
sulfhydration or sulfuration of free cysteine residues (S-SH bonds).37,38
There is no FDA approved antidote for H2S. MB, with its potential
rescuing effects on the mitochondrial activity, has been tried as an antidote
against H2S intoxication.39
Methylene blue and its reduced metabolite LMB interact with the
mitochondrial complexes and can antagonize the formation excess of
ROS by H2S. MB promotes transfer of protons through the mitochondrial

membrane, against a concentration gradient, thus helping in the production
of ATP needed for mitochondrial respiration. MB has shown to counteract
the H2S toxicity-induced cardiac depression by cardiac ion channel
dysfunction and ATP reduction.40
Low dose MB (0.5 mg/kg) was reported to be beneficial for a 4-year-
old child of shock following polytrauma that was refractory to volume
replacement and maximal vasoactive support.41
AS AN INDICATOR DYE
The anesthesiologists have utilized MB for a variety of procedures because of
its distinct color, which can be easily appreciated against the normal tissue
and for being nontoxic as an indicator dye. Interestingly, MB does not cause
an increase in blood pressure when it is used as a dye in nonvasoplegic
patients. It has been noted that MB exerts its vasoconstrictive effect only
in the states of NO upregulation.3
A few examples of the studies that have used MB as an indicator dye in
patients are:
• To study bronchial mucus transport velocity42 (mucociliary function)
during pharyngeal spread of topical local anesthetic administered orally
during general anesthesia in children by mixing lignocaine with MB,43 to
detect gastric aspiration while comparing different supraglottic devices,44
the spreading patterns from the paravertebral space using a solution of
MB and local anesthetic.45
• It has been used in cadaveric studies to see the spread of drugs in
different anatomical planes like the serratus anterior plane block,46
thoracic paravertebral space,47 etc.
ADVERSE EFFECTS
Although rare, complications are described in literature following the use
of MB, which can be potentially fatal.
Rarely, MB may cause shortness of breath, tremors, vomiting, bluish
discoloration of body fluids, and hemolytic anemia in very high doses. Serious
complications noted with the use of MB include coronary vasoconstriction,
increases in pulmonary vascular resistance, and decreases in splanchnic
blood flow. These vasoconstrictive states in multiple organ systems are
explained by the global antagonism of NO-mediated vasodilation.23
Mesenteric perfusion decreases with high dose (7 mg/kg) of MB. Slight
increase in serum glutamic pyruvic transaminase has been observed for a
transient phase. Increase in pulmonary vascular resistance and interference
in gas exchange occur with the use of MB in large doses.21
Methylene blue and LMB are excreted in the urine, giving it a green
color and the sclera might also get bluish coloration.
While MB is being used to treat vasoplegia and various shocks like
states, it is important for the anesthetist to know that MB itself might cause
anaphylactic shock.48
SEROTONIN TOXICITY
Serotonin toxicity is caused by the excess of serotonergic drugs or interaction
with inhibitors of serotonin metabolism like monoamine oxidase inhibitors
(MAOI).4
The signs and symptoms of serotonin toxicity are caused due to
stimulation of 5-hydroxytryptamine (5-HT) and can be broadly divided into
three categories:
1. Altered mental status (agitation, excitement, confusion, and coma).
2. Altered neuromuscular excitability (tremor, clonus, hyperreflexia,
myoclonus, and pyramidal rigidity).
3. Autonomic instability (tachypnea, tachycardia, hyperthermia, dia
phoresis, and mydriasis).
Life-threatening serotonin toxicity has been reported after administering
MB to treat VS, in patients on chronic selective serotonin reuptake inhibitor
(SSRI) therapy, and had undergone cardiac surgery.49
Methylene blue has an MAOI activity, with an important MAO-A
inhibition, thus reducing synaptic clearance of serotonin. After being
absorbed rapidly in the nervous system, it reaches high concentrations in
the brain tissue after intravenous administration. The major metabolite of
MB, azure-B, is a potent inhibitor of MAO-A and MAO-B, further enhancing
the serotonergic activity of this drug.
• US FDA Safety Communication Recommendations:
▪▪ In emergency situations: Alternative vasopressor to MB should
be considered. If MB has to be used then stop serotonergic drugs
immediately and monitor patients for emergent symptoms of central
nervous system (CNS) toxicity for 2 weeks (5 weeks for fluoxetine) or
until 24 hours of the last dose of MB, whichever comes first.
▪▪ In nonemergency situations: When MB is contemplated for use,
serotonergic psychiatric medication should be stopped 2 weeks in
advance (5 weeks for fluoxetine) of MB treatment. Serotonergic drugs
can be resumed after 24 hours of the last dose of MB.24,50
CONTRAINDICATIONS
Absolute contraindications for the use of MB are for severe hypersensitivity
to MB and in patients with G6PD deficiency as it can precipitate hemolytic
anemia.3,17
Caution should be exercised while using MB in patients with compromised

renal and hepatic function. The drug is excreted mostly by the kidneys and
extensively metabolized by the liver, therefore if used; such patients should
be monitored for a longer time.17 MB should preferably be avoided in the
presence of pulmonary hypertension and acute lung injury.4
CONCLUSION
Methylene blue is valuable in anesthesia and intensive care practice.
It serves as an antidote for MHgb, it is effective as a noncatecholamine
vasopressor in refractory shock, and it has also proved useful in the
management of ifosfamide toxicity and hydrogen sulfite poisoning. Serious
complications might occur if used injudiciously. Controversies and lack of
definite guideline for its use in a variety of clinical scenarios will exist till
further research clears the existing doubts.
KEY POINTS
• Methylene blue has been an integral part of the treatment regime of
acquired MHgb.
• In MHgb, it acts as a reducing agent to convert methemoglobin to
hemoglobin.
• It is beneficial in the treatment of refractory vasoplegia arising after major
cardiovascular surgery.
• Methylene blue has served as a rescue therapy in varied types of
distributive shock when conventional therapy with fluids and catecholamine
vasopressors fail.
• It acts by blocking the nitrous oxide-cyclic GMP pathway of vasodilatation.
• Antineoplastic agent, ifosfamide toxicity is reversed to certain extent
by MB.
• Serotonin syndrome is a major complication of methylene blue treatment
in patients taking serotonergic drugs.
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cardiovascular collapse. J Emerg Med. 2014;46(5):670-9.
3. Hosseinian L, Weiner M, Levin MA, et al. Methylene blue: magic bullet for
vasoplegia? Anesth Analg. 2016;122(1):194-201.
4. Jang DH, Nelson LS, Hoffman RS. Methylene blue for distributive shock: a
potential new use of an old antidote. J Med Toxicol. 2013;9(3):242-9.
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6. Carrodeguas L, Szomstein S, Jacobs J, et al. Topical anesthesia-induced
methemoglobinemia in bariatric surgery patients. Obes Surg. 2005;15(2):282-5.
7. Kuiper-Prins E, Kerkhof GF, Reijnen CG, et al. A 12-day-old boy with methemo
globinemia after circumcision with local anesthesia (lidocaine/prilocaine).
Drug Saf Case Rep. 2016;3(1):12.
8. McRobb CM, Holt DW. Methylene blue-induced methemoglobinemia during
cardiopulmonary bypass? A case report and literature review. J Extra Corpor
Technol. 2008;40(3):206-14.
9. Zeng LA, Hwang NC. Vasoplegia: more magic bullets? J Cardiothorac Vasc
Anesth. 2019;33(5):1308-9.
10. McCartney SL, Duce L, Ghadimi K. Intraoperative vasoplegia: methylene blue
to the rescue! Curr Opin Anaesthesiol. 2018;31(1):43-9.
11. Licker M, Diaper J, Robert J, et al. Effects of methylene blue on propofol
requirement during anaesthesia induction and surgery. Anaesthesia.
2008;63(4):352-7.
12. Miyawaki I, Nakamura K, Yokubol B, et al. Suppression of cyclic guanosine
monophosphate formation in rat cerebellar slices by propofol, ketamine and
midazolam. Can J Anaesth. 1997;44:1301-7.
13. Masaki E, Kondo I. Methylene blue, a soluble guanylyl cyclase inhibitor,
reduces the sevoflurane minimum alveolar anesthetic concentration and
decreases the brain cyclic guanosine monophosphate content in rats. Anesth
Analg. 1999;89:484-9.
14. Senthilnathan M, Cherian A, Balachander H, et al. Role of methylene blue
in the maintenance of postinduction hemodynamic status in patients with
perforation peritonitis: a pilot study. Anesth Essays Res. 2017;11(3):665-9.
15. Baraka AS, Ayoub CM, Yazbeck-Karam V, et al. Prophylactic methylene blue
in a patient with congenital methemoglobinemia. Can J Anaesth. 2005;52(3):
258-61.
16. Hariharan U, Sood R, Choudhury A, et al. Oxygen desaturation following
methylene blue injection: Not always spurious. Saudi J Anaesth. 2011;5(1):
113-4.
17. Matisoff J, Panni MK. Methylene blue treatment for methemoglobinemia and
subsequent dramatic bispectral index reduction. Anesthesiology. 2006;105:228.
18. Yamaji F, Soeda A, Shibata H, et al. A new mutation of congenital methemo
globinemia exacerbated after methylene blue treatment. Acute Med Surg.
2018;5(2):199-201.
19. Belletti A, Musu M, Silvetti S, et al. Non-adrenergic vasopressors in patients
with or at risk for vasodilatory shock. A systematic review and meta-analysis
of randomized trials. PLoS One. 2015;10(11):e0142605.
20. Pasin L, Umbrello M, Greco T, et al. Methylene blue as a vasopressor: a meta-
analysis of randomised trials. Crit Care Resusc. 2013;15(1):42-8.
21. Habib AM, Elsherbeny AG, Almehizia RA. Methylene blue for vasoplegic
Syndrome postcardiac surgery. Indian J Crit Care Med. 2018;22(3):168-73.
22. Fischer GW, Levin MA. Vasoplegia during cardiac surgery: current concepts
and management. Semin Thorac Cardiovasc Surg. 2010;22:140-4.
23. Shaefi S, Mittel A, Klick J, et al. Vasoplegia After Cardiovascular Procedures-
Pathophysiology and Targeted Therapy. J Cardiothorac Vasc Anesth. 2018;
32(2):1013-22.
24. Ortoleva JP, Cobey FC. A systematic approach to the treatment of vasoplegia
based on recent advances in pharmacotherapy. J Cardiothorac Vasc Anesth.
2019;33(5):1310-4.
25. Raikhelkar JK, Weiss AJ, Maysick L, et al. Adjuvant therapy with methylene
blue in the treatment of postoperative vasoplegic syndrome caused by
carcinoid crisis after tricuspid valve replacement. J Cardiothorac Vasc Anesth.
2012;26(5):878-9.
26. Lutjen DL, Arndt KL. Methylene blue to treat vasoplegia due to a severe
protamine reaction: a case report. AANA J. 2012;80(3):170-3.
27. Bhalla T, Sawardekar A, Russell H, et al. The role of methylene blue in the
pediatric patient with vasoplegic syndrome. World J Pediatr Congenit Heart
Surg. 2011;2(4):652-5.
28. Evora PR, Alves Junior L, Ferreira CA, et al. Twenty years of vasoplegic syndrome
treatment in heart surgery. Methylene blue revised. Rev Bras Cir Cardiovasc.
2015;30(1):84-92.
29. Mehaffey JH, Johnston LE, Hawkins RB, et al. Methylene blue for vasoplegic
syndrome after cardiac operation: early administration improves survival. Ann
Thorac Surg. 2017;104:36-41.
30. Mazzeffi M, Hammer B, Chen E, et al. Methylene blue for postcardiopulmonary
bypass vasoplegic syndrome: a cohort study. Ann Card Anaesth. 2017;20:
178-81.
31. Koelzow H, Gedney JA, Baumann J, et al. The effect of methylene blue on the
hemodynamic changes during ischemia reperfusion injury in orthotopic liver
transplantation. Anesth Analg. 2002;94(4):824-9.
32. Fukazawa K, Pretto EA. The effect of methylene blue during orthoptic liver
transplantation on post reperfusion syndrome and postoperative graft function.
J Hepatobiliary Pancreat Sci. 2011;18(3):406-13.
33. Jang DH, Nelson LS, Hoffman RS. Methylene blue in the treatment of refractory
shock from an amlodipine overdose. Ann Emerg Med. 2011;58(6):565-7.
34. Pelgrims J, De Vos F, Van den Brande J, et al. Methylene blue in the treatment
and prevention of ifosfamide-induced encephalopathy: report of 12 cases and
a review of the literature. Br J Cancer. 2000;82(2):291-4.
35. Shin YJ, Kim JY, Moon JW, et al. Fatal ifosfamide-induced metabolic
encephalopathy in patients with recurrent epithelial ovarian cancer: report of
two cases. Cancer Res Treat. 2011;43(4):260-3.
36. Kataria PS, Kendre PP, Patel AA. Ifosfamide induced Encephalopathy
Precipitated by Aprepitant: A Rarely Manifested Side Effect of Drug Interaction.
J Pharmacol Pharmacother. 2017;8(1):38-40.
37. Haouzi P, Sonobe T, Judenherc-Haouzi A. Developing effective countermeasures
against acute hydrogen sulfide intoxication: challenges and limitations. Ann N
Y Acad Sci. 2016;1374(1):29-40.
38. Haouzi P, Sonobe T, Judenherc-Haouzi A. Hydrogen sulfide intoxication
induced brain injury and methylene blue. Neurobiol Dis. 2019;104474. [Epub
ahead of print].
39. Ng PC, Hendry-Hofer TB, Witeof AE, et al. Hydrogen Sulfide Toxicity: Mechanism
of Action, Clinical Presentation, and Countermeasure Development. J Med
Toxicol. 2019. [Epub ahead of print].
40. Cheung JY, Wang J, Zhang XQ, et al. Methylene Blue Counteracts H2S-Induced
Cardiac Ion Channel Dysfunction and ATP Reduction. Cardiovasc Toxicol.
2018;18(5):407-19.
41. Volpon LC, Evora PRB, Teixeira GD, et al. Methylene blue for refractory shock
in polytraumatized patient: a case report. J Emerg Med. 2018;55(4):553-8.
42. Seo H, Kim SH, Choi JH, et al. Effect of heated humidified ventilation on
bronchial mucus transport velocity in general anaesthesia: a randomized trial.
J Int Med Res. 2014;42(6):1222-31.
43. Beringer R, Skeahan N, Sheppard S, et al. Study to assess the laryngeal and
pharyngeal spread of topical local anesthetic administered orally during
general anesthesia in children. Paediatr Anaesth. 2010;20(8):757-62.
44. Polat R, Aydin GB, Ergil J, et al. [Comparison of the i-gel™ and the Laryngeal
Mask Airway Classic™ in terms of clinical performance]. Rev Bras Anestesiol.
2015;65(5):343-8.
45. Agnoletti V, Piraccini E, Corso R, et al. Methylene blue diffusion after multilevel
thoracic paravertebral blocks. J Cardiothorac Vasc Anesth. 2011;25(2):e5-6.
46. Biswas A, Castanov V, Li Z, et al. Serratus Plane Block: A Cadaveric Study to
Evaluate Optimal Injectate Spread. Reg Anesth Pain Med. 2018;43(8):854-8.
47. Sabouri AS, Crawford L, Bick SK, et al. Is a Retrolaminar Approach to the
Thoracic Paravertebral Space Possible?: A Human Cadaveric Study. Reg Anesth
Pain Med. 2018;43(8):864-8.
48. Dewachter P, Mouton-Faivre C, Tréchot P, et al. Severe anaphylactic shock with
methylene blue instillation. Anesth Analg. 2005;101(1):149-50.
49. Martino EA, Winterton D, Nardelli P, et al. The Blue Coma: The Role of
Methylene Blue in Unexplained Coma After Cardiac Surgery. J Cardiothorac
Vasc Anesth. 2016;30(2):423-7.
50. Grubb KJ, Kennedy JL, Bergin JD, et al. The role of methylene blue in serotonin
syndrome following cardiac transplantation: a case report and review of the
literature. J Thorac Cardiovasc Surg. 2012;144(5):e113-6.
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CHAPTER
25 Journal Scan
Kirti N Saxena, Shreya Goswami, Purnima Dhar, Anup Gogia
JOURNAL SCAN 1—Kirti N Saxena

Preoperative Echocardiography for Patients with Hip Fractures Under
going Surgery: A Retrospective Cohort Study Using a Nationwide
Database.
Yonekura H, Ide K, Onishi Y et al. Anesth Analg. 2019;128(2):213-20.
BACKGROUND
Elderly patients have a high incidence of comorbidities with significant
cardiopulmonary involvement. Transthoracic echocardiography (TTE) is
an important tool for the assessment of cardiac function. However, it is
not clear if its routine preanesthetic use can affect the clinical outcomes
of patients. The authors hypothesized that preoperative TTE is associated
with reduced postoperative morbidity and improved patient survival after
surgical repair of hip fractures.
ABSTRACT
In this retrospective study, records of 66,620 patients who underwent
hip fracture surgery within 2 days of admission, over an 8-year period
(2008–2016), were examined from a nationwide administrative database.
The association of preoperative echocardiography with the incidence
of in-hospital mortality was analyzed using propensity score matching.
The incidence of postoperative complications, intensive care unit (ICU)
admissions and length of hospital stay were also examined as secondary
outcomes. Overall 52.1% patients underwent preoperative TEE screening.
The propensity score matched to nonscreened patients did not show
in-hospital mortality differences (P = 0.45). There was no reduction in
postoperative complications and ICU admissions (P = 0.53). Findings were
also consistent with other sensitivity analyses and subgroup analyses.
The duration of hospital stay was more in those who underwent TTE
compared to those who did not. The authors concluded that preoperative
echocardiography was not associated with reduced in-hospital mortality or
postoperative complications.
COMMENTARY
It is well known that elderly patients form a large percentage of those suffering
from hip fractures. This population has a high incidence of comorbidities
such as pulmonary and cardiac diseases. Due to the advanced age of
these patients, they may not give function-related history after sustaining
fractures. Perioperative concerns are more in these patients since geriatric
patients have a number of comorbidities.
Cardiac and lung diseases have major implications for the postoperative
outcome. TTE is an important tool for the assessment of cardiac function.
However, most guidelines such as those of the American heart association
(AHA) recommend the use of TTE as a diagnostic tool for heart disease
after clinical assessment suggests compromised cardiac function.1 Several
multivariate risk scores such as American College of Surgeons National
Surgical Quality Improvement Program (NSQIP) Surgical Risk Calculator
and the Duke activity status index (DASI) have been suggested to assess
the perioperative risk of a major adverse cardiac event (MACE) of death
or myocardial infarction (MI). These indices take into account the age,
functional status, comorbidities, type of surgery, whether emergent or
elective and biochemical parameters. Recent literature suggests that
assessment of geriatric patients should not be focused on single systems
but must be comprehensive including comorbidities with their medical
management, nutritional and mental health, functional capacity, social
circumstances, and surgery-specific risk scores.2
Several reviews on the use of preoperative TTE have suggested definite
indications for it, with reduced functional capacity before the surgical
condition being a strong indicator for it. They failed to report any evidence
that routine preoperative evaluation using TTE can result in improved
outcomes in geriatric patients postoperatively.3 Contrary to this, Bøtker et
al. in a prospective study found that preoperative focused cardiopulmonary
ultrasound revealed unexpected pathologies and recommended it routinely
for elderly patients.4 This argument was carried further by Heiberg et al. who
conducted a meta-analysis of retrospective studies on this subject.5 They
included studies on patients admitted in intensive care as well as those
undergoing surgery. They found that focused cardiac ultrasonography had
the potential to change the diagnosis as well as the interventions resulting
from it. Since most of the studies were retrospective in nature, they concluded
that well-designed prospective studies were required to conclusively decide
whether TTE should be made part of the routine preoperative screening of
surgical patients.
Undiagnosed cardiopulmonary disease is likely to result in increased
postoperative complications. Based on a previous study6 which showed a
rise in Troponin T levels following surgery for fracture femur suggesting
Journal Scan 379
a perioperative cardiac event, Yonekura in their article opined that

preoperative TTE would help in uncovering any undiagnosed heart disease
that may not have manifested in this group of patients. However, there is
a paucity of studies demonstrating a clear link between preoperative TTE
and improved postoperative outcomes.
This retrospective cohort study was conducted using multiple claims
database of diagnosis, procedure, and combination data of patients
above 60 years of age admitted between 2008 and 2016 in acute care
hospitals in Japan. Hip fracture was clearly defined (fracture of the femoral
neck or intertrochantric fracture), and only those patients undergoing
surgery defined as the open reduction of fracture with internal fixation,
hemiarthroplasty, or total hip arthroplasty were included in the analysis.
Preoperative data included the type of fracture and operative procedure,
the status of the patient on admission, and any medical intervention
before surgery. The comorbidities were evaluated using the Charlson and
Elixhauser comorbidity scores. Two groups were compared fulfilling these
criteria: those who underwent TTE before surgery and those who did not.
The primary outcome was defined as mortality and secondary outcome was
cardiopulmonary complications, postoperative admission to intensive care
unit (ICU) and length of hospital stay.
The results of the study showed that there was no significant difference
in the primary outcome, that is, in-hospital mortality in the two groups.
There was no significant difference in the postoperative complications
and admission to ICU between the groups. ICU admissions reflect serious
postoperative morbidity with no difference between the groups. The only
difference was that the length of hospital stay both before and after surgery
was significantly higher in the group that underwent TTE preoperatively
compared to the group that did not. They ascribed this to increased medical
interventions in these patients and suggested prospective studies to find
whether TTE should be done routinely in elderly patients undergoing surgery.
The results need cautious analysis since TTE can alter the course
of management of the surgical patients. However, this may lead to early
medical intervention benefitting certain patients. This may have resulted
in significantly increased length of stay of patients preoperatively due to
medical interventions. This retrospective study may help in guiding future
prospective studies. The shortcomings of the study as pointed out by the
authors are that firstly, strict exclusion criteria were used so the results
cannot be generalized. Secondly, this study was conducted in Japan where
patients are admitted for longer periods in hospital compared to Western
countries. Better access to healthcare and better socioeconomic status of
Japanese patients result in lower mortality rates compared to those across
the world. Thirdly, the database has a certain degree of anonymity and failed
to identify any association between certain groups of surgeons being more

likely to order a TTE before surgery.
To conclude, preoperative TTE was found to have no association with
in-hospital mortality in elderly patients undergoing surgery for hip fracture.
Further prospective studies are needed.
REFERENCES
1. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline
on perioperative cardiovascular evaluation and management of patients
undergoing noncardiac surgery: a report of the American College of Cardiology/
American Heart Association Task Force on practice guidelines. J Am Coll
Cardiol. 2014;64(22):e77-137.
2. Chan SP, Ip KY, Irwin MG. Peri-operative optimisation of elderly and frail
patients: a narrative review. Anaesthesia. 2019;74(Suppl 1):80-9.
3. Shim CY. Preoperative cardiac evaluation with transthoracic echocardiography
before non-cardiac surgery. Korean J Anesthesiol. 2017;70(4):390-7.
4. Bøtker MT, Vang ML, Grøfte T, et al. Routine pre‐operative focused
ultrasonography by anesthesiologists in patients undergoing urgent surgical
procedures. Acta Anaesthesiol Scand. 2014;58(7):807-14.
5. Heiberg J, El-Ansary D, Canty DJ, et al. Focused echocardiography: a systematic
review of diagnostic and clinical decision-making in anaesthesia and critical
care. Anaesthesia. 2016;71(9):1091-100.
6. Dawson-Bowling S, Chettiar K, Cottam H, et al. Troponin T as a predictive
marker of morbidity in patients with fractured neck of femur. Injury. 2008;39(7):
775-80.
JOURNAL SCAN 2—Shreya Goswami

Post-anaesthesia pulmonary complications after use of muscle relaxants
(POPULAR): a multicentre, prospective observational study.
Kirmeier E, Eriksson LI, Lewald H, et al. POPULAR Contributors.
Lancet Respir Med. 2019;7(2):129-40.
BACKGROUND
Postoperative pulmonary complications (POPC) are one of the most
common, serious adverse events affecting a significant number of patients
undergoing surgery under general anesthesia. It was first suggested that
inadequate antagonism of neuromuscular blockers (NMBs) may contribute
to postoperative pulmonary adverse events.1 There is now evidence
that almost 75% of the patients receiving NMB develop some form of
alteration in the respiratory mechanics and it takes 6 weeks to return to the
preoperative physiological state.2 Among the various risk factors of POPC,
NMBs are considered to have a significant contribution. The present study
was conducted to assess the role of NMBs in producing POPC and whether
the use of reversal agents and intraoperative neuromuscular monitoring,
can assist to alleviate POPC.
Journal Scan 381
ABSTRACT
Postoperative pulmonary complications can be widely defined as conditions
affecting the respiratory system contributing to the postoperative morbidity
and mortality of patients after surgery. The incidence of POPC widely varies
between 1% and 23% and the suggested incidence of POPC even surpasses
the cardiac complications.2
This multicenter prospective observational cohort study looked at
whether the patient receiving NMB are at increased risk of developing
postoperative pulmonary complications and whether the use of antagonism
of neuromuscular blockade or neuromuscular monitoring can prevent POPC.
Data from 22,803 patients from 211 hospitals in 28 European countries were
collected. Patients ≥ 18 years posted for noncardiac surgery under general
anesthesia were included and patients’ demographics, perioperative details,
and chart review at discharge were prospectively collected over 2 weeks. The
primary outcome was the incidence of POPC up to 28 days after surgery.
The study found 7.6% increased incidence of POPC in patients who
received NMBs. About 2.3% patients with high risk (both surgical and
respiratory) were not administered any NMBs. The investigators observed
that the use of neuromuscular monitoring and extubation at a train of four
(TOF) ratio of 0.9 or more, as well as the use of reversal, were not associated
with a decrease in POPC. Interestingly the use of sugammadex instead of
neostigmine did not prove to be beneficial in alleviating POPC. Hence, the
overall potential benefits of neuromuscular blockade need to be balanced
against the increased risk of POPC.
COMMENTARY
Postoperative pulmonary complications is a broad term attributed to any
complication involving the respiratory system after surgery increasing the
morbidity and mortality of the patient. The authors of the current study used
the predictive model formulated by Canet et al.3 to prognosticate POPC.
The predictive index was based on any one of the following complications
like respiratory failure, bronchospasm, atelectasis, pleural effusion,
pneumothorax or aspiration pneumonitis. Their study demonstrated a 5%
incidence of POPC with an increase in 30-day mortality in such patients. The
index served as a risk assessment tool to assess POPC in patients scheduled
for surgery.3,4
The authors in their study (POPULAR) observed that among the
multiple modifiable and nonmodifiable factors, NMBs are considered to
have a significant contribution to the development of POPC. This is the first
retrospective study of such high magnitude to provide prospective data for the
role of NMBs in developing POPC. The study is well designed and adequately
powered. In order to obtain a standardized and uniform data collection, a
constant collaboration between the national and local coordinators were

ensured and any queries throughout the study were continuously addressed.
The plan for statistical analysis was thorough. PERISCOPE study by Canet
et al.3,4 was used as a reference for sample size calculation. The authors tried
to negate the effects of multiple confounding factors like surgery per se as
well as patient’s preoperative comorbid conditions that can independently
contribute to the development of POPC. The researchers included the
known causes of POPC as confounding variables in data analysis. Logistic
regression was used and further sensitivity analysis was carried out to
negate the effects of confounder variables which could modify the result of
the study. Adjusted values of odds ratio (ORadj) and absolute risk reduction
(ARRadj) were provided.
However, in my view, cardiorespiratory reserves of the patients
included in the study may not have been the same. Some of them may
have been on regular physical exercise schedule as a part of their daily
routine. There is evidence now to show that patients who are subjected
to physical “conditioning” prior to operative stresses (prehabilitation) with
exercise and incentive spirometry have enhanced functional capacity and
lesser propensity to develop POPC.5 The incidence of POPC is less even
when enhanced recovery after surgery (ERAS) protocol is used.6 There is
no mention about the following situations in the present study which have
the potential to modify the end result of the study.
The authors of the POPULAR study defined the following seven key
factors for the analysis of neuromuscular management: use of NMBs,
expected duration of blockade, use of neuromuscular monitoring technique
(quantitative vs qualitative), adherence to the recommended TOF 0.9 or
more for extubation of trachea, use of reversal agents and type of reversal
used (neostigmine vs sugammadex). The investigators constructed five
subcohorts as all the seven key factors were not applicable to all the
patients. The subcohorts are: patients receiving general anesthesia, the
patient receiving NMBs, patients receiving neuromuscular monitoring
(quantitative versus qualitative), and patients receiving a reversal agent. The
POPULAR study demonstrated that the use of neuromuscular blockade was
associated with an increased incidence of POPC and even a single dose of
NMB contributed to the development of POPC. This finding correlates with
the previous retrospective studies which have also found the association
of POPC with the use of NMBs.7 However, the multivariate analysis could
not confirm any association between duration of NMBs and the use of a
high dose of NMBs with development of POPC. It is prudent to observe
that preservation of the tone of diaphragm plays a significant role in the
preservation of lung volume and reserve. Once the diaphragm is paralyzed
(even if it is a single dose of NMB), basal atelectasis can be induced.8
Hence, maneuvers to retain lung volume have to be employed to ensure
Journal Scan 383
these atelectatic areas are expanded by repeated recruitment maneuvers

in addition to continuous positive end-expiratory pressure (PEEP). These
maneuvers ought to be undertaken during mechanical ventilation and
before extubation to show an impact on the incidence of POPC.9 A still
more useful and balanced approach can be to employ regional anesthesia
techniques along with general anesthesia which is widely practiced in ERAS
multispecialty protocols.
The study demonstrated that the use of neuromuscular monitoring,
both qualitative as well as quantitative (tracheal extubation on TOF ≥ 0.9)
does not decrease the incidence of POPC. The use of reversal also has a
similar finding. Both neostigmine and sugammadex failed to alleviate the
risk of POPC in patients receiving neuromuscular blockade. This contradicts
the finding of Brueckmann and colleagues, who looked at the reversal
of rocuronium-induced neuromuscular blockade by sugammadex after
abdominal surgery. The incidence of residual blockade (TOF < 0.9) and
operating room discharge readiness were recorded. The study showed that
sugammadex administration abolished residual neuromuscular blockade in
the postanesthesia care unit and stepped up the discharge readiness of the
study population.10
To conclude, the POPULAR study has consolidated on the evidence that
NMBs are associated with an increased incidence of POPC. Hence, it is
prudent to limit the usage of NMBs to provide surgical relaxation, avoid
indiscriminate use in short surgeries and in patients with minor risk factors
to decrease the risk of POPC in those patient population. If used, the author
recommends the use of recruitment maneuvers and PEEP to restore the
lung volume repeatedly during mechanical ventilation and just before
extubation.
ACKNOWLEDGMENT
The author would like to express her gratitude to Professor Pankaj Kundra
for his valuable inputs and his contribution for this write-up.
REFERENCES
1. Berg H, Roed J, Viby-Mogensen J, et al. Residual neuromuscular block is a risk
factor for postoperative pulmonary complications. A prospective, randomised,
and blinded study of postoperative pulmonary complications after atracurium,
vecuronium and pancuronium. Acta Anaesthesiol Scand. 1997;41(9):1095-103.
2. Miscovic A, Lumb AB. Postoperative pulmonary complications. Br J Anaesth.
2017;118(3):317-34.
3. Canet J, Gallart L, Gomar C, et al. Prediction of postoperative pulmonary
complications in a population-based surgical cohort. Anesthesiology.
2010;113(6):1338-50.
4. Canet J, Sabaté S, Mazo V, et al. Development and validation of a score to

predict postoperative respiratory failure in a multicentre European cohort: A
prospective, observational study. Eur J Anaesthesiol. 2015;32(7):458-70.
5. Kundra P, Vitheeswaran M, Nagappa M, et al. Effect of preoperative and
postoperative incentive spirometry on lung functions after laparoscopic
cholecystectomy. Surg Laparosc Endosc Percutan Tech. 2010;20(3):170-2.
6. Gillis C, Li C, Lee L, et al. Prehabilitation versus rehabilitation: a randomized
control trial in patients undergoing colorectal resection for cancer.
Anesthesiology. 2014;121(5):937-47.
7. Bulka CM, Terekhov MA, Martin BJ, et al. Nondepolarizing Neuromuscular
Blocking Agents, Reversal, and Risk of Postoperative Pneumonia. Anesthesiology.
2016;125(4):647-55.
8. Kundra P, Subramani Y, Ravishankar M, et al. Cardiorespiratory effects
of balancing PEEP with intra-abdominal pressures during laparoscopic
cholecystectomy. Surg Laparosc Endosc Percutan Tech. 2014;24(3):232-9.
9. Kundra P, Garg R, Patwa A, et al. All India Difficult Airway Association 2016
guidelines for the management of anticipated difficult extubation. Indian J
Anaesth. 2016;60:915-21.
10. Brueckmann B, Sasaki N, Grobara P, et al. Effects of sugammadex on incidence
of postoperative residual neuromuscular blockade: a randomized, controlled
study. Br J Anaesth. 2015;115:743-51.
JOURNAL SCAN 3—Purnima Dhar

Perioperative Quality Initiative consensus statement on intraoperative
blood pressure, risk and outcomes for elective surgery.
Sessler DI, Bloomston JA, Aronson S, et al. Perioperative Quality Initiative-3
workgroup.
Br J Anaesth. 2019:122(5):563-74.
BACKGROUND
Research in anesthesia is largely about reducing the morbidity and
mortality after surgery. Over the years, there has been a drastic reduction
in perioperative mortality and morbidity due to various improvements in
preoperative assessment, intraoperative monitoring, and postoperative
care. However, the medium- and long-term outcomes continue to be a
source of concern. Severe hypotension/hypertension as a cause of adverse
postoperative outcome is understandable, but the patients who survive
the immediate postoperative period may die later of acute kidney injury,
MI, stroke, or sepsis. There is mounting evidence that one of the factors
which may cause any of these may be extended periods of less than severe
hypotension intraoperatively. The effect of intraoperative hypotension on
organ functions has been a subject of research ever since we started doing
deliberate hypotension for ease of surgery. But there has been a lack of
consensus on the definition of unacceptable intraoperative hypotension. A
varying incidence of intraoperative hypotension, ranging from 5% to 99%
Journal Scan 385
was reported in a meta-analysis published in 2004.1 The lack of consensus

on the definition of intraoperative hypotension may be responsible for
the very wide range in the number of adverse outcomes that have been
previously reported in the literature.2 However, despite the widely-presumed
importance of blood pressure management during the perioperative period,
doubts have also been raised.3
This consensus statement was hence needed to clarify and answer the
usual questions one faces every day while conducting anesthesia and put
at least some doubts to rest.
ABSTRACT
There is evidence that long-term outcomes after surgery can be due to blood
pressure fluctuations. To collect the evidence and formulate a consensus on
the issue of intraoperative blood pressure a Perioperative Quality Initiative
Consensus-Building Conference was held in London in July 2017. Eleven
experts from the world over and the Perioperative Quality Initiative-3
workgroup were involved in the process. They used the modified Delphi
method and came out with three consensus statements. The article has
details of the consensus statements and also talks about the issues where
consensus was not reached and therefore need further research.
COMMENTARY
Effect of intraoperative blood pressure fluctuations, especially hypotension,
on kidneys, heart, and brain (and other organs) has been addressed
many times before by individual institutions. This time, it comes from
Perioperative Quality Initiative (POQI), an international multidisciplinary
nonprofit organization that organizes consensus conferences on topics of
interest related to perioperative medicine. For this consensus, the modified
Delphi method was used. In this method, all possible questions regarding
a topic are raised over several rounds and sent to a panel of experts. The
anonymous responses are shared with the group. An extensive review of
literature is done and opinions shared. Finally, they seek to reach a correct
response through a consensus at a conference. Four papers on different
aspects of perioperative blood pressure have been published regarding
physiology, preoperative control, intraoperative control, and postoperative
management of blood pressure. This scan is about the consensus statement
on intraoperative blood pressure management.
The authors have come out with three consensus statements. The first
consensus statement tries to define intraoperative hypotension. It states:
Consensus statement 1: “Intraoperative mean arterial blood pressures below
60–70 mm Hg are associated with myocardial injury, acute kidney injury,
and death. Systolic arterial pressures below 100 mm Hg are associated with
myocardial injury and death. Injury is a function of hypotension severity
and duration.”
The statement has confined itself to absolute threshold values. The
threshold relative to preoperative blood pressure values is not clearly defined.
Several studies reviewed have taken a fall of ≥20% as a threshold while others
have taken ≥30% and even 40% as a threshold. As the blood pressures are
taken immediately preoperatively are often unreliable and real preoperative
blood pressures often unavailable, the panel concurs with Salmasi et al.
that the associations based on relative thresholds were no stronger than
those based on absolute thresholds.4 They did not find clinically important
interaction with preoperative pressure and have concluded that anesthetic
management can be based on intraoperative pressure without regard to
preoperative pressure.4 However, a large prospective multicenter trial used
the baseline blood pressure as received from the medical records and found
the best outcome results with tight control (±10% of baseline) in high-risk
patients.5
A meta-analysis of studies in orthopedic patients finds support for
the use of deliberate hypotension in reducing blood loss and transfusion
requirements in orthopedic surgery,6 but these results are tempered by the
small sample sizes and poor methodological quality of published studies.2
The panel is not very clear about the management strategy for tachycardia.
A recent retrospective study found no relationship between heart rate and
outcomes7 and the panel seems to endorse that. The study concluded that
there was no apparent association between various measures of tachycardia
and a composite of myocardial injury after noncardiac surgery (MINS)
and death,7 a result that contradicts previously reported associations. So,
the study showing that a tachycardia of more than 100 beats/min is an
independent factor for adverse outcomes in long-duration surgeries,8 has
not been given credence in the final statement which clubs tachycardia
of more than 100 beats/min with hypotension to predict increased organ-
specific risks.2 The statement regarding inadvisability of treating tachycardia
at the cost of causing hypotension is important and hence gives guidance.2
There is no clear guidance regarding the duration of hypotension in
the consensus statement. One of the quoted studies on 1-year mortality in
elderly patients confirms the clinical experience that besides the absolute
or relative blood pressure thresholds, the duration of low blood pressure is
equally important in the possible association of intraoperative hypotension
with adverse outcome, i.e. lower blood pressures were tolerated for shorter
durations.9
Consensus statement 2 deals with intraoperative hypertension in
noncardiac surgery and states:
Journal Scan 387
Consensus statement 2: “For adults having noncardiac surgery, there is

insufficient evidence to recommend a general upper limit of blood pressure
at which therapy should be initiated.”
The statement fails to give us a clear upper limit of systolic/mean blood
pressure above which the outcome suffers. Going through the eight studies
analyzed for intraoperative hypertension, a systolic blood pressure of more
than 160 mm Hg seems to be the cut-off most authors have taken. Recent
trials are equivocal about there being any adverse postoperative outcome
with intraoperative hypertension. Data available from a secondary analysis
of the vascular events in noncardiac surgery cohort evaluation (VISION) trial
suggest that intraoperative systolic arterial pressures (SAP) >160 mm Hg are
associated with myocardial injury and infarction.2 But a large retrospective
analysis of >52,000 adults, noncardiac surgical patients reported that those
with mean arterial pressure (MAP) >120 mm Hg did not exhibit complications
within the perioperative period. Contrary to common belief, increased
lability was associated with decreased 30-day mortality.10
The panel found paucity and heterogeneity of the published evidence
and conclude that a general upper limit of blood pressure at which therapy
should be initiated remains to be defined. “Overall, the available data suggest
that elevated intraoperative blood pressures are not as strongly associated
with postoperative morbidity as hypotension. That said, intraoperative
arterial pressure management should be individualized in consideration of
underlying organ function and the surgical procedure being performed.”2
The consensus statement 3 is about intraoperative hypertension in
cardiac surgery.
Consensus statement 3: “During cardiac surgery, intraoperative systolic
blood pressure greater than 140 mm Hg is associated with increased 30-day
mortality. Injury is a function of severity and duration.”
The panel seems to have based their statement on two independent
studies and there is a clear message. The importance of preoperative pulse
pressure being a surrogate of vascular health is emphasized. The panel
finds evidence that preoperative pulse pressure >70–80 mm Hg is a good
predictor for stroke, cardiac complications, and death.2
Besides these consensus statements, the panel has listed unanswered
questions and recommends research in these areas. Some of these
questions include: What is the safe lower/upper limit of blood pressure?
Which component of blood pressure is more important? How long can one
give deliberate hypotension? Which drugs are safer for treating hypotension?
Which patients/situations are more vulnerable?
Overall, the article is important, as it emphasizes issues related to the
importance of maintaining intraoperative blood pressure and defining
thresholds for the same. In addition, the authors have also identified key
areas for further research.
REFERENCES
1. Howell SJ. Consensus statements and expert guidance: interpret with care. Br
J Anaesth. 2019;122:719-22.
2. Sessler DI, Bloomstone JA, Aronson S, et al. Perioperative quality initiative
consensus statement on intraoperative blood pressure, risk and outcomes for
elective surgery. Br J Anaesth. 2019;122:563-74.
3. Li D, Bohringer C, Liu H. What is “normal” intraoperative blood pressure
and do deviations from it really affect postoperative outcome? J Biomed Res.
2017;31(2):79-81.
4. Salmasi V, Maheshwari K, Yang D, et al. Relationship between Intraoperative
Hypotension, Defined by Either Reduction from Baseline or Absolute
Thresholds, and Acute Kidney and Myocardial Injury after Noncardiac Surgery:
A Retrospective Cohort Analysis. Anesthesiology. 2017;126(1):47-65.
5. Futier E, Lefrant JY, Guinot PG, et al. Effect of Individualized vs Standard Blood
Pressure Management Strategies on Postoperative Organ Dysfunction Among
High-Risk Patients Undergoing Major Surgery: A Randomized Clinical Trial.
JAMA. 2017;318(14):1346-57.
6. Paul JE, Ling E, Lalonde C, et al. Deliberate hypotension in orthopedic
surgery reduces blood loss and transfusion requirements: a meta-analysis of
randomized controlled trials. Can J Anesthes. 2007;54:799-810.
7. Ruetzier K, Yilmaz HO, Turan A, et al. Intra-operative tachycardia is not
associated with a composite of myocardial injury and mortality after noncardiac
surgery: A retrospective cohort analysis. Eur J Anaesthesiol. 2019;36(2):105-13.
8. Reich DL, Bennett-Guerrero E, Bodian CA, et al. Intraoperative tachycardia
and hypertension are independently associated with adverse outcome in
noncardiac surgery of long duration. Anesth Analg. 2002;95:273-7.
9. Bijker JB, van Klei WAV, Vergouwe Y, et al. Intraoperative hypotension and
1-year mortality after noncardiac surgery. Anesthesiology. 2009;111:1217-26.
10. Levin M, Fischer G, Lin HM, et al. Intraoperative arterial blood pressure lability
is associated with improved 30 day survival. Br J Anaesth. 2015;115(5):716-26.
JOURNAL SCAN 4—Anup Gogia

Effect on Morphine Requirement of Early Administration of Oral
Acetaminophen vs. Acetaminophen/Tramadol Combination in Acute Pain.
Bouida W, Beltaief K, Msolli MA, et al. Pain Pract. 2019;19(3):275-82.
BACKGROUND
Pain is considered as fifth vital sign and is often the presenting complaint
in the emergency department. However, despite an armamentarium
of available analgesics, pain remains inadequately managed leading to
patient dissatisfaction. Opioids are mainstay of treating severe pain but are
associated with serious side effects including hypoxia, hypotension, abuse
potential, and even death. Use of multiple drugs with different mechanisms
of action can be effective in reducing the opioid dose and related side
effects. The authors studied the impact of starting acetaminophen or
Journal Scan 389
tramadol/acetaminophen combination on morphine requirement and

patient satisfaction in emergency department.
ABSTRACT
In this multicentric, randomized, single blind trial, patients over 18 years
of age with pain [Visual analog scale (VAS) equal to or higher than 30/100]
in triage area were included. Patients were randomly assigned to receive
either placebo, acetaminophen (1000 mg) or tramadol/acetaminophen
combination (75 mg/650 mg). Primary outcome measure was need for
rescue morphine during emergency department (ED) stay. Secondary
outcome included patient satisfaction regarding overall management
quality in the ED, ED length of stay and percentage of patients discharged
from the ED with VAS < 30. Visual analog scale pain score assessment was
repeated 30 minutes after the medications were given and at ED discharge.
Patients having VAS > 70 at 30 minutes post triage assessment were given
intravenous (IV) morphine as rescue analgesia. Patients having a VAS score
between 30 and 70 at 30 minutes triages were given first step analgesics at
the discretion of the treating physician. A total of 1,485 patients completed
the study (mean age 37.9 years). In 54.15% of participants pain was traumatic
in origin. The mean VAS at triage was comparable in all three groups as
well as between trauma and non-trauma pain patients (63 ± 14 vs 63 ± 15).
The mean VAS decrease 30 minutes post triage was statistically significant
between group tramadol/acetaminophen combination and group placebo
but not significant between group acetaminophen and placebo (P < 0.001).
The difference between group tramadol/acetaminophen combination
and group acetaminophen was not significant (P = 0.59). The difference
in the need for rescue morphine was significant only between tramadol/
acetaminophen combination and placebo group. Emergency department
length of stay was significantly shorter in tramadol/acetaminophen group
compared to other groups. Patient satisfaction was highest in tramadol/
acetaminophen group (77%), compared to acetaminophen group (69%)
and placebo groups (68%). The difference in the percentage of patients
discharged with VAS score <30 was only significant between acetaminophen
and tramadol/acetaminophen group (P = 0.01). The authors concluded that
tramadol/acetaminophen combination at triage significantly decreases use
of recue morphine with higher rate of patient satisfaction compared to
acetaminophen alone or placebo.
COMMENTARY
Pain is the most common presenting complaint in ED. Whereas ED specialist
is concerned about differential diagnosis and ruling out life threatening
issues, pain relief is of paramount significance to the patient. Administration
of analgesics is often delayed till diagnosis is made. Simple procedures like

venepuncture and cannulation add to the agony of the patient. This leaves
the patients in distress further delaying the diagnosis and treatment.
Factors that lead to sub-optimal pain management are overcrowding in
ED, delay in first dose, inadequate dose, lack of reassessment of pain and
lack of protocol based management. As a result many of the patients leave
ED dissatisfied. This issue of delayed and sub-optimal pain management was
labeled as “Oligoanalgesia in ED’’ and led to increase in opioid prescriptions
in 1990s.1
A multicentric study involving 842 patients was done by Todd et al. in
2007 to evaluate pain management practice in ED of 20 US and Canadian
hospitals. Patients presented with pain score ranging between 4 and 10 with
median score of 8. Only 60% of these patients received analgesics. There was
a median 90 minutes delay in analgesic administration and reassessment
was poor. Majority of the patients (74%) were discharged in moderate to
severe pain. Opioids particularly morphine was the most common analgesic
prescribed.2
Results of above study show that pain continues to be treated sub-
optimally despite increase in opioid use. There is a two fold increase in the
number of opioid prescriptions from 1998 to 2011.
In recent years, there has been a concern regarding side effects of
opioids and their abuse potential particularly related to use in emergency
department. There is a four-fold increase in deaths from opioid related
overdose in USA from 1999 to 2010. In 2010, 16,665 people died from opioid-
related overdoses.
Hoppe et al. studied initiation of opioids in emergency and its recurrent
use. They observed that opioid naïve patients treated in ED with opioids
for acute pain are more likely to be using opioids 1-year later. In another
study, patients at risk of developing dependence were found to be the ones
having history of past or current nicotine use or other substance abuse.3,4
Clinical practice guidelines and hospital protocols are being developed
using alternative analgesics to reduce opioid use.
For optimal pain management it is important to understand pain
mechanisms and use of multiple analgesics to target possible pain
pathways. With the use of combination of analgesic drugs targeting different
receptors, optimal pain control can be achieved with reduced individual
drug requirement and hence, fewer side effects. This concept of multimodal
analgesic regime (balanced analgesia) is based on Channels, Enzymes,
Receptors, Targeted, Analgesia (CERTA). CERTA involves use of opioid and
non-opioid analgesics to target different pain pathways so that individual
dose can be reduced to improve patient safety.5,6
Journal Scan 391
Cohen et al. studied opioid sparing protocol in the emergency department

based on CERTA. Pain management was done using IV ketorolac and oral
ibuprofen. During the study period, patients with acute and chronic pain
were found to be satisfied with pain relief using CERTA based protocol with
no adverse effects.7
Benefits of CERTA based analgesia have also been observed in patients
admitted in emergency department with renal colic. There was reduction
in opioid administration in ED by 12.7% and at discharge by 25.5%.8
An analgesic pyramid approach has been suggested which includes
stepwise approach and involves use of opioids as the pain severity is
increased. Various analgesics can be used in combination, with target
being any of these channels, enzymes and receptors like COX-1, COX-II
inhibitors, TRV1 receptor agonists, sodium channel blockers, dopamine
receptor antagonists, glutamate/NMDA (N-methyl-D-asparate) receptor
antagonists, gamma-aminobutyric acid (GABA) receptor agonists, serotonin
receptor agonists, calcium channel blockers, mu receptor agonists, central
alpha-2 receptor agonists.5,6
Tramadol and acetaminophen is one such combination which is used
to treat moderate to severe pain. Acetaminophen acts on central and
peripheral pathways with exact mechanism of action not fully known.
Proposed mechanisms are cyclo-oxygenase inhibition, NMDA receptor
inhibition and serotonergic antagonism in the central nervous system.
Acetaminophen alone is effective for mild pain and has weak opioid sparing
effects. Tramadol is a weak mu receptor agonist, inhibits serotonin and
nor-adrenaline uptake. It is used in moderate to severe pain. Advantage of
tramadol is its effectiveness in both nociceptive and neuropathic pain. Side
effects associated with tramadol can be nausea, agitation, hypertension,
hypoglycemia, hyponatremia, and lowering of seizure threshold.
Combination of tramadol and acetaminophen has shown synergy and
supra additive effects in both animals and human pain model studies.9 A
combination of tramadol and acetaminophen provides onset of action as
rapid as paracetamol and duration as long lasting as tramadol. These drugs
undergo metabolism using separate metabolic pathways.
Dhillon et al. reviewed several clinical studies exploring clinical efficacy
of tramadol and acetaminophen combination. This combination has
been found to be effective as well as tolerated in both acute and chronic
pain conditions like musculoskeletal pain, postoperative pain, diabetic
neuropathy, headache, and other chronic pain conditions.10
McQuay et al. did a meta-analysis of tramadol and acetaminophen
combination in acute postoperative pain of moderate to severe intensity.
This meta-analysis shows analgesic superiority of combination over
individual drugs with no additional side effects. Side effects observed were
of individual drugs and included dizziness, drowsiness, nausea, vomiting
and headache.11
An important limitation of the study by Bouida et al. is that it is not powered

to comment on reduction in opioid related side effect with tramadol-
acetaminophen combination as compared to acetaminophen or placebo. As
participants in this study are mostly young adults, this study fails to address
effect of tramadol-acetaminophen combination in extremes of ages. It has
been found that these groups are most affected in terms of inadequate
dosage as well as risk of adverse effects. The drugs in this particular study
have been used by oral route only thus limiting its efficacy. An intravenous
route would have been faster acting, reliable and more efficacious.
Pharmacodynamic activity of tramadol depends on CYP2D6 activity and
thus tramadol and other weak opioids have variable efficacy as compared
to strong opioids, but nevertheless carry the risk of respiratory depression
and abuse potential.12 Bush et al. have reported an increase in emergency
visits related to adverse reactions associated with tramadol use in data
available with drug abuse and warning network (DAWN).13 This also is
related to the fact that tramadol prescription has increased 88% from 2008
to 2013. Thus, long-term effects of tramadol paracetamol combination need
to be assessed. There is a need of further studies to establish comparative
efficacy and tolerability of tramadol-paracetamol combination to other
combinations available in the market.
Other commonly used combination is tramadol with diclofenac. Tramadol
and diclofenac combination has been compared to tramadol-paracetamol
combination in patients with acute musculoskeletal pain, postoperative
pain, and acute flare of osteoarthritis and rheumatoid arthritis. Primary end
point being reduction in pain intensity. Fixed-dose combination (FDC) of
tramadol-diclofenac was found to be better in reducing pain intensity and
was well tolerated as compared to tramadol-paracetamol.14
Long-term effects use of nonsteroidal anti-inflammatory drugs (NSAIDs)
can lead to side effects. It has been suggested by Pergolizzi et al. that
tramadol-paracetamol combination may be used to avoid long-term and
high-dose treatment with NSAIDS or NSAIDS paracetamol combination in
chronic pain conditions.15
In 2018, a questionnaire based study was done in southeast Asian
countries to study use of tramadol in pain practice. Results of this study
show that tramadol and tramadol containing combinations are commonly
used in management of moderate to severe pain as a safe alternative to high
dose NSAIDs or opioids like morphine or codeine.16
Other emerging alternative opioid sparing pain management strategies in
ED include use of regional nerve blocks, nitrous oxide, sub-dissociative dose
of ketamine, gabapentinoids and IV lignocaine. In addition to analgesic use,
other factors like frequent pain assessments, protocol based management
along with use of non-technical/soft skills like showing empathy to the
patient and patient centerd communication can bridge the gap between
patient expectations and what ED physicians can offer.17
Journal Scan 393
To conclude, tramadol and acetaminophen has emerged as a promising

analgesic combination in the management of moderate to severe pain,
whether acute or chronic in nature. The concept is to combine drugs from
different classes to provide a better analgesia at reduced doses of individual
agents with an opiate-sparing effect. Few things need to be kept in mind
are its contra indications, side effects, its variable clinical response and risk
of abuse potential. Long-term effects of tramadol-paracetamol combination
need to be assessed as well as there is a need to establish its comparative
efficacy and tolerability to other analgesic modalities available in ED.
REFERENCES
1. Wilson JE, Pendleton JM. Oligoanalgesia in the emergency department. Am J
Emerg Med. 1989;7(6):620-3.
2. Todd KH, Ducharme J, Choiniere M, et al. Pain in the emergency department:
results of the pain and emergency medicine initiative (PEMI) multicenter
study. J Pain. 2007;8(6):460–6.
3. Hoppe JA, Kim H, Heard K. Association of emergency department opioid
initiation with recurrent opioid use. Ann Emerg Med. 2015;65(5):493-9.
4. Hooten WM, St Sauver JL, McGree ME, et al. Incidence and Risk Factors for
Progression From Short-term to Episodic or Long-term Opioid Prescribing: A
Population-Based Study. Mayo Clin Proc. 2015;90(7):850-6.
5. Hosseininejad SM, Amini Ahidashti H, Bozorgi F, et al. Efficacy and Safety
of Combination Therapy with Ketorolac and Morphine in Patient with Acute
Renal Colic; A Triple-Blind Randomized Controlled Clinical Trial. Bull Emerg
Trauma. 2017;5(3):165-70.
6. Cisewski DH, Motov SM. Essential pharmacological options for acute
pain management in the emergency setting. Turk J Emerg Med. 2019;
19:1-11.
7. Cohen V, Motov S, Rockoff B, et al. Development of an opioid reduction protocol
in an emergency department. Am J Health Syst Pharm. 2015;72(23):2080-6.
8. Motov S, Drapkin J, Butt M, et al. Analgesic Administration for Patients with
Renal Colic in the Emergency Department Before and After Implementation
of an Opioid Reduction Initiative. West J Emerg Med. 2018;19(6):1028-35.
9. Filitz J, Ihmsen H, Günther W, et al. Supra-additive effects of tramadol and
acetaminoiphen in human pain model. Pain. 2008;136(3):262-70.
10. Dhillon S. Tramadol/paracetamol fixed-dose combination: a review of its use
in the management of moderate to severe pain. Clin Drug Investig. 2010;30
(10):711-38.
11. McQuay H, Edwards J. Meta-analysis of single dose oral tramadol plus
acetaminophen in acute postoperative pain. Eur J Anaesthesiol Suppl. 2003;
28:19-22.
12. Rodieux F, Vutskits L, Klara M Posfay-Barbe, et al. When the Safe Alternative
Is Not That Safe: Tramadol Prescribing in Children. Front Pharmacol. 2018;
9: 148.
13. Bush DM. Emergency Department Visits for Adverse Reactions Involving the
Pain Medication Tramadol. The CBHSQ Report. Rockville (MD): Substance
Abuse and Mental Health Services Administration (US); 2013. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK343538/”.
14. Chandanwale AS, Sundar S, Latchoumibady K, et al. Efficacy and safety profile
of combination of tramadol-diclofenac versus tramadol-paracetamol in patients
with acute musculoskeletal conditions, postoperative pain, and acute flare of
osteoarthritis and rheumatoid arthritis: a Phase III, 5-day open-label study.
J Pain Res. 2014;7:455-63.
15. Pergolizzi JV Jr, van de Laar M, Langford R, et al. Tramadol/paracetamol
fixed combination in the treatment of moderate to severe pain. J Pain Res.
2012;5:327-46.
16. Vijayan R, Afshan G, Bashir K, et al. Tramadol: a valuable treatment for pain
in Southeast Asian countries. J Pain Res 2018;24(11):2567-75.
17. Todd KH. A Review of Current and Emerging Approaches to Pain Management
in the Emergency Department. Pain Ther. 2017;6:193–202.
Index 395
Index
Page numbers followed by b refer to box, f refer to figure,
fc refer to flowchart, and t refer to table
A handling unit 329

hunger 309
Abdominal compartment syndrome 117 lock phenomenon 102
Abdominal distension 126 sampling 346
Abdominal examination 126 warming appliance 332
Abnormal maternal-fetal antigen- Airborne
antibody reaction 37 particles 340
Acarbose 231 pathogenic agents 149
Acclimatization 323 Airway 40, 71
leads 314 compromise, surgery for 287
period of 318 manipulation 277
Acetaminophen 391
obstruction 58, 79
Acetazolamide 324
trauma, risk of 294
Acetylcholine 157
Alarm fatigue 155
Acidosis 117
Albumin levels 126
Acinetobacter 332, 340
Alfentanil 168, 193
Acromioclavicular joint 354, 356
Allergies 146, 149
Acromion process 355, 356
Alpha glucosidase 231
Active warming mechanisms 198
Alpha-amino-3-hydroxy-5-methyl-4-
Acute coronary syndrome 216, 319
Acute high-altitude illness 308, 310 isoxazolepropionic acid 157
Acute hypoxemic respiratory failure 281 Alveolar anesthetic concentration 365
Acute mountain sickness 308 Alzheimer’s disease 27
Acute respiratory American Academy of Orthopaedic
distress syndrome 122 Surgeons 206
failure, treatment of 174 American Association of Clinical
Adaptive support ventilation 179 Endocrinologists 234, 237
Adipocyte 70 American Association of Nurse
subcutaneous 70 Anesthesiologist 151
Adjunctive therapy 122 American College of Obstetricians and
Adjustable pressure limiting valve 346 Gynecologists 70, 166
Adrenergic receptors 366 American College of Physicians 234, 237
Adrenocorticotropic hormone 228 American Diabetes Association 226,
Afferent thermal sensing 191 230, 234
Agitation 372, 391 Consensus Statement on Inpatient
Air Glycemic Control 237
blower 329 American Heart Association 219, 378
conditioning American National Standards Institute
compressor 329 330
engineers 330 American National Surgical Quality
emboli, retrograde ascent of 101 Improvement Program 28
American Society for Parenteral and development of 257

Enteral Nutrition 116 endovascular management of 266
American Society of Anesthesiologists posterior circulation 259
31, 87, 92, 150, 196, 221, 247 rupture 257, 258, 266
American Society of Heating intraoperative 266
Refrigerating 330 site of 257, 259
American Society of Interventional Pain Angiography 219
Physicians 209 coronary 215
Amino acid 121 intraoperative 265
glutamine 123 pre-embolization 272f
Analgesia 250 Angiotensin-converting enzyme
neuraxial 71 inhibitors 220
Anaphylactic reactions 368 Anterior cruciate ligament 209
Anaphylaxis 59, 60, 368 Antiangiogenic proteins 38
severe 368 Antibiotic prophylaxis 346
Anemia 87, 221 Anticholinesterase inhibitors 55
Anesthesia 4, 88, 248, 363 Anticipate 70
considerations 272 Anticoagulation 268
devices 345 myth of 60
disinfection of 348 Antihypertensives 50
effect of 157 Antioxidant 123
equipment 341, 345 therapy 40
for cesarean section 77 Apnea 164
for labor 71 Apoptosis 165
for neurovascular procedures 256 Arrhythmia
indications in 284 causation of 366
induction of 79, 264 ventricular 215
inhalational 293 Arterial air embolism 101
local infiltration 249 Arterial blood 312
maintenance of 267 gas analysis reveals 104
medication errors in 10 oxygen saturation of 309
neuraxial 193 pressure 258
obstetric 288 Arterial gas embolism 104
practice of 10 Arterial oxygen saturation 181
procedures in 284 Arterial waveform-derived cardiac
types of 227 output 219
work area 347 Arteriovenous malformation 256, 268,
Anesthesiologists 273
bacterial contamination of 137 clinical features 270
health hazards for 145 diagnosis 271
Anesthetic grading of 269
agents, mechanism of action of 158t incidence 269
drugs 29, 228 management strategies 271
machine, alarms on 8 radio intervention 271
management 47 surgical excision of brain 271
practice 13 with elevated risk of bleeding and
technique 29 rebleeding 270
workforce, large proportion of 150 Artery
Aneurysm 256 anterior communicating 259
common site of 257 posterior communicating 259
Index 397
Arthritis 25 Birth
Arthroscopy 357 trauma 72
Aspiration weight, low 161
and development, risk of 120 Blind approach 301
prophylaxis 49 Blood 136, 314
Aspirin 250 brain barrier 370
therapy 39 glucose 226, 227, 228, 235, 235t, 240
Associations of Perioperative Registered concentrations 237t
Nurses 345 levels 235
Atelectasis 58, 79 pressure 181
Atopy 149 control of 43
Atrial septal defects 316 diastolic 35, 36
Atropine 228 management 261
Attention-deficit disorder 162 non-invasive 50
Australia and New Zealand College of systolic 35, 36, 175, 261
Anaesthesia 12 sugar 239
Automated external defibrillators 134 levels 227
Automatic tube compensation 177, 178 vessels
Autonomic instability 372 embolic obstruction of 101
Awake fiberoptic intubation 286 results 101
Axilla 340 Bloodstream infection 122
Axillary nerve 354, 355, 356, 359 Body
anterior approach 359 fluids, discoloration of 371
inferior axilla 359 mass index 39, 69, 122
posterior approach 359 average 286
temperature, monitoring of 192
Bone loss 247
B Bowel obstruction 117
Back pain, low 206, 207 Brachial plexus
Balloon block 358
angioplasty 261 costoclavicular 358
tipped blocker 294 infraclavicular 359
Barbiturates 158 retroclavicular 359
Barometric pressures, ambient 100 branches of 354f
Baroreceptor reflex 229 cords 360
Basal skull fracture 281 posterior cord 354
Bayley developmental scale 164 Bradycardia 102
Benzodiazepines 92, 93, 158 Brain
use of 153 natriuretic peptide 319
Benzylisoquinolinium fumarate diester neurotransmitters in 157
62 relaxation 265
Beta-blockers 229 Breath, shortness of 371
Biguanides 231 Bronchial cuff of right-sided double-
Biliary cirrhosis, primary 111 lumen tubes, modification of
Biomarkers 93, 218 299f
Biomedical waste 347 Bronchoconstriction 182
Biphasic positive airway pressure 80 Bronchoscope, pediatric 294
Bronchospasm 62 oxygen delivery 313

B-type natriuretic peptide 185 perfusion 108
pressure 261, 262
salt wasting syndrome 261
C vasospasm, balloon angioplasty of
Calabadion 63 273
Calcium 30, 128 veins 101
channel blockers 391 vessels 104
deficiency 38 Cerebrospinal fluid 77, 195
supplementation 40 drain, opening of 258
Capnography 111 Cerebrovascular accidents 226
Carbon dioxide 99, 111, 279 Certified Registered Nurse Anesthetists
arterial pressure of 309 151
breathed out, volume of 118 Cervical
high partial pressure of 104 spine 100
partial pressure of 74, 312 superficial plexus 357
Cardiac depression, toxicity-induced Cesarean delivery 71, 109
371 Challenging several traditional imaging
Cardiac diseases 378 techniques 135
Cardiac index 27 Charge acidic groups 55
Cardiac ion channel dysfunction 371 Chest
Cardiac ischemic symptoms 215 computerized tomography of 319
Cardiac pathology, absence of 182 radiography 319
Cardiac surgery 238, 366, 372 Chlorine, replacement of 62
Cardiac system 182 Cholecalciferol 30
Cardiogenic acute pulmonary edema Chronic mountain sickness 308
283 Chronic obstructive pulmonary disease
Cardiomyopathy 72 178, 279
Cardiopulmonary disease 378 Chronic pain 87
Cardiovascular collapse 102 management of 203
Cardiovascular disease 87 Circadian rhythm 191
Cardiovascular drug poisoning 369 Circle of Willis 257f, 258
Cardiovascular manifestations 40 Circulation 313
Cardiovascular system 27, 75, 260 Cisatracurium 13
Carlens tube with carinal hook 295f Claustrophobia 280
Catecholamines 366 Clonus 372
Central laboratory device 238 Coagulation 268
Central nervous system 36, 103, 256, profile 263
260, 391 Cold ambient temperatures 316
disorders 161 Collapse
manifestations 41 consolidation 182
Central respiratory drive 176 prevention of 304
Central venous catheter 106, 110 Coma 372
placement 221 Complete blood count 89, 263
Cerebral Compliance rate oxygenation and
circulation 313 pressure index 176, 177
edema 108 Comprehensive geriatric assessment 28
high-altitude 308 Computer-aided decision-making
irritation 41 system and electronic reminders
ischemia, delayed 260 333
Index 399
Confusion 372 risk factors for 94

assessment method 90 screening 89
Continuous femoral nerve blocks 248 Delivery, timing of 42b
Continuous positive airway pressure Dementia 27, 91, 95
72, 177, 279, 293, 321 Depression 91
Continuous subcutaneous insulin Desflurane 158
infusion 232, 233 Dexamethasone 322, 324
Contraceptive mechanism of action of 322
hormonal 61 Dexmedetomidine 158, 167, 193
use 61 Dextrose 121
Coracoid process 355, 356 Diabetes 87
Coronary artery 104 Control and Complications Trial
bypass grafting 367 227
disease 217, 247 gestational 72
revascularization prophylaxis trial mellitus 25, 71, 75, 226
220 Diaphoresis 372
Corticosteroid, role of 185 Diarrhea 117
Costoclavicular block 357 Diazepam 160
Cranial nerve deficit 259 Digital subtraction angiography 263
C-reactive protein 93
Dipeptidyl peptidase-4 232
Cricoid pressure 75
Disinfection 341
Critical care units 153
levels of 345
Cyanosis, central 317
low-level 345
Cyclic guanosine monophosphate 364
Disseminated intravascular coagulation
degradation of 322
41, 42, 46
Cyclooxygenase 250
Distractions 137
inhibition 391
issues of 141
Cysteine 63
Cytochrome p450 370 source of 138
Distress 215
Dizziness 310, 391
D Dopamine 157
Danish Birth Cohort Study 162 receptor antagonists 391
Daycare arthroplasty 244 Double-lumen airway 300
Daycare surgery 238 Double-lumen endotracheal tubes 293,
bane of 85 296, 299, 304, 305
context of 85 Double-lumen tubes
Daycare total joint arthroplasty 245 history of 295
Deep breathing exercises 80 left-sided 301
Deep venous thrombosis 250 recent advances in 303
prophylaxis 250 right-sided 298f
risk of 73 use of 294
Deficit accumulation 23, 24 Drowsiness 391
Degenerative diseases 203 Drug errors, classification of 14t
Dehydroepiandrosterone 30 Duchenne-Muscular dystrophy 58
Delirium 86, 88 Duke activity status index 378
elderly at-risk instrument 92t Dysglycemia 226
features of 86 Dysphagia postextubation, detection
precipitate 86 of 126
preventing 93t Dyspnea 287, 317
E Epidural anesthesia 48, 78

Epithelial growth factor 204
Eclampsia 34, 36 Errors in medicine 1
treatment of 46 active 2
Edema
causation of 8
subclinical pulmonary 319
changing approach to 7
subglottic 40
classification of 2
Edmonton frail scale 24
Ejection fraction 27 description 3
Electric blanket 198 fixation error 3
Electrocardiogram 182, 260, 319 incidence 2
Electrocardiographic changes 106, 215, lapse 3
218 latent 4
Electrocardiography 134 mode 3
Electroencephalogram 357 sequence 3
delta waves on 87 slips 3
Electrolytes Erythropoietin, release of 314
like sodium, concentration of 126 Ethanol 160
monitoring 125 Ethylene oxide sterilization 345
Electronic data, application of 333 Etomidate 158, 228
Electronic medical records 135
European Society for Clinical Nutrition
Elevated pulmonary artery wedge
and Metabolism 116
pressure 219
Elevated serum transaminases 36 Exenatide 231
Embolism 111 Experimental therapies 109
Emphasis 1 Expiratory positive airway pressure 321
Employ regional anesthesia techniques Extracorporeal membrane oxygenation
383 117, 221
Encephalopathy, ifosfamide-induced
369
Endocannabinoids 157
F
Endocrine Facet joint 208
abnormalities 183 Fat
function 70 absorption of 120
Endometritis 73 globules of 102
Endorphins 157 Fatigue 310
Endothelial nitric oxide 314 Fatty acid, essential 128
Endotracheal tube, removal of 174 Fatty tissue 28
Endovascular therapy 273
Fentanyl 76, 160, 168, 267
Endovascular treatment 262, 272
Fetal
End-tidal nitrogen 103, 105
growth restriction 36
Enhanced recovery after surgery 232
heart monitoring 50
244
Enteral nutrition 115, 117b, 119 macrosomia 72
benefits of 117b surveillance 43
dosing of 119 Fetus, delivery of 42
Entonox 76 Fever, low-grade 317
Enzymes, release of 101 Fiber 123
Ephedrine 49 Fiberoptic bronchoscope guided 301
Epidural analgesia 47, 80, 193 Fiberoptic bronchoscopy 302
block neuronal impulses 193 Fire and accidents 147, 153
Index 401
Fisher Scale Based on Computed Gastrointestinal endoscopy 100

Tomography Appearance for Gastrointestinal system 75
Subarachnoid Hemorrhage Gastrostomy, percutaneous endoscopic
260t 119
Fixation errors, types of 3 General and regional anesthetic
Fluid techniques 293
and electrolyte imbalance 261 General anesthesia 47, 71, 78, 163,
management, role of 185 190, 193, 227, 267, 285
therapy 45 amount of 357
Food and Drug Administration 63, 151, considerations 49
365
Genetic
Forced expiratory volume 74
and collagen disorders 257
Forced-air blankets 198
and epigenetic variation 316
Frail body 26
inheritance 37
Frail organ system 26
Frailty 22 Genicular nerve blocks 205
demographic and social factors 26 Geriatric nursing assessment and
functional factors 25 intervention 94
implications of 26 Gestations, multiple 69
index 24 Glasgow coma scale 260
pathophysiology of 25 score 259
physiological factors 25, 26 Glenohumeral joint 356
risk factors for 25 capsule, quadrants of 355f
Functional neurological deficits 246 Glibenclamide 231
Functional residual capacity 282 Glimepiride 231
Glipizide 231
G Global Anesthesiology Server Network
136
G6PD deficiency 364, 372 Global positioning systems 133
Gabapentins 250 Gloves, microperforation of 332
Gamma-aminobutyric acid 157, 158, Glucagon-like peptide 1 232
391 agonists 231
levels of 86 Glucose
Gantacurium 62 insulin-potassium 235
Gas embolism 99, 100 monitoring 125
clinical presentation 103
Glutamate 391
detection 104
Glutamine 123
differential diagnosis 106
Glycemic control 240
epidemiology 99
Glycemic goals in perioperative period
etiology 100
management 107 229
pathophysiology 101 Glycemic management in
prevention 106 intraoperative period 234
Gas flow controls 346 postoperative period 236
Gastric Glycosylated fibronectin serum levels
aspirate 117 38
banding 57 Gordon-green double-lumen tube 296,
emptying 78 296f
residual volume 126 Guanylate cyclase activity 365
continuous monitoring of 120 Gut ischemia 117
H High-flow nasal cannula, role of 185

High-flow nasal oxygen 277-279, 289
Hammer blow 258 components of 280f
Hand hygiene 347 equipment for 278
nonperformance of 333 in critical care, indications of 281
Hand sanitizers 140 Hindsight bias 8
Hazards 152 Hip fracture 379
Headache 41, 258, 309, 310 Histamine 62, 368
Hearing 92
Hormone angiotensin 70
disability 155
Human error, causes of 6
impairment 94
Human immunodeficiency virus 136,
Heart
149
disease, ischemic 75
failure 247 Humeral head 356
acute decompensated 318 Hunt and Hess classification 259t
congestive 44, 75 Hyaluronic acid, intra-articular 205
incidence of 27 Hydralazine 44
Heat shock protein 316 Hydrocephalus 260
Heating gel pad 198 Hydrogen sulfide 370
Heating ventilation and air toxicity 370
conditioning system 328, 329 Hyperactivity disorder 162
Hemodialysis 125 Hyperbaric chambers 320
Hemoglobin 43 Hyperbaric oxygen therapy 109
concentration 314 Hyperdynamic circulation 40
molecule 364 Hyperglycemia 226, 240
normal 364 management of 226
Hemolysis, elevated liver enzymes, and perioperative 226
low platelets syndrome 34, 36, Hypernatremia 261
42, 51 Hyperreflexia 41, 372
Hemorrhage Hypersensitivity 59, 60
hepatic 36 Hypertension 35, 71, 391
postpartum 73 acute management of 44
pulmonary 182 chronic 35, 43
subarachnoid 257t gestational 35
Hepatic dysfunction 36, 122 high-altitude pulmonary 308
Hepatic failure 125 in pregnancy 35
Hepatitis
postpartum 37
B viruses 149
pregnancy-induced 34, 35, 39, 51, 72
C viruses 149
primary pulmonary 316
Hiatal hernia 75
refractory 50
High pulmonary
capillary permeability 314 Hyperthermia 372
vascular resistance 311 Hyperuricemia 41
High-altitude pulmonary edema 308, Hypocaloric feeding 115
311, 314, 317, 319 Hypoglycemia 236, 391
clinical presentation 317 Hypoglycemic episodes 226
differential diagnosis 319 Hypokalemia 183
investigations 318 Hypomagnesemia 183
pathophysiology 314 Hyponatremia 391
prevention 323 exercise-associated 319
treatment 320 Hypophosphatemia 123, 183
Index 403
Hypotension 218, 386 Integrated multiple variables index 176

deliberate 384, 387 Intensive care 363
intraoperative 385 unit 92, 115, 127, 145, 173, 194,
Hypothalamic ischemia 261 230, 248, 278, 283, 377, 379
Hypothermia 193 Interleukin 70, 217
inadvertent perioperative 190, 194 Internal carotid artery, intercavernous
intraoperative 196 259
Hypothesis 22 International Commission on
system integration failure 86 Radiological Protection 148
Hypoxemia 58, 283, 364 International Subarachnoid Aneurysm
arterial 317 Trial 262
worsening 117 Interscalene block 353
Hypoxia 218 Interventional neuroradiology,
alveolar 314 evolvement of 256
inducible factor 314, 316 Intervertebral disk degeneration 203
perinatal 161 Intestinal contents, aspiration of 117
prevention of 284 Intra-abdominal pressure 77, 126
treatment in 277 Intra-aortic balloon pump 221
Hypoxic pulmonary vasoconstriction Intra-arterial stenting 261
308 Intra-arterial vasodilator therapy 261
Hysteroscopy 110 Intracranial aneurysm 256, 258, 259t
management of 274
specific features of 259t
I Intracranial pressure 261, 262, 273
Iatrogenic pressure 100 Intradiskal injection 207, 208
Ifosfamide 370 Intraoperative blood pressure 387
toxicity 369 fluctuations, effect of 385
Immobilization 94 management 385
Immune modulators 123 Intrapulmonary shunting 101
Immunoglobulin E 149 Intrauterine
Inclusion 94 devices 61
Indian armed forces acclimatization growth restriction 42
schedule 312t Intravenous administration sets 107
Induction 263 Intrinsic positive end-expiratory
Infections 149 pressure 279
control measure 329 Invasive blood pressure monitoring 50
healthcare-associated 332 Invasive central hemodynamic
Inflammation, chronic 73 monitoring 50
Inflammatory cell 70 Ionizing radiation 267
Inflow ducts 329 Ipsilateral phrenic nerve 353
Infraspinous fossa 356 Iron, oxidation of 364
Inhalational agent 29, 76, 228 Ischemia
Injury 173 causes of 219
Inspired oxygen, fraction of 176, 181, reperfusion injury 369
279 Ischemic angina pain 215
Insulin Ischemic evaluation, perioperative 220
infusion 235t Isocaloric feeding 115
intermediate-acting 233 Isoflurane 158, 160
regimen 233 Isophosphoramide mustard 370
subcutaneous 234 Isoquinolinium muscle 62
J Lignocaine 267
Linagliptin 231, 232
James reason’s Swiss cheese model of Lipids 121
causation of errors 5 Lipophilic cavity 55
Jet ventilation, high-frequency 304 Liraglutide 231
Joint Association of Obstetric Liver 373
Anesthesiologists 288 function 125
Joint British Diabetes Societies 230 tests 126
Inpatient Care Group 239 Local anesthetic toxicity, occurrence
of 353
K Long chain triglyceride 128
Low back pain, chronic 206, 209
Ketamine 158, 160, 228 Low bispectral index 29
Ketoacidosis, diabetic 226, 239 Low minimum alveolar concentration
Ketonemia 239 29
Kidney Low molecular weight heparins 80, 250
disease, chronic 246 Lung 182
injury, acute 122, 385 conditions, chronic 182
Knee arthroplasty, unicompartmental diseases 378
245 injury, acute 373
water, excessive 182
L
Labetalol 44, 267
M
Labor analgesia 46, 76 Magnesium sulfate 45, 50, 51
Lake Louise acute mountain sickness Major adverse cardiac event 220, 378
score 310t Major cardiovascular surgery 366
Lake Louise criteria for MallinckrodtTM double-lumen tubes
classification of high altitude 309t 297, 298f
clinical diagnosis of high-altitude Malnutrition
pulmonary edema 309t patients at risk of 116
Laminar airflow 332t universal screening tool 116
plenum 329 Malpractice claims 147, 152
Laminectomy 100 Maternal stabilization 51
Laparoscopy 111 Maxillofacial trauma 281
Laryngoscope’s light bulb, failure of 134 Maximum allowable concentration 330
Latex allergy 149 Maximum inspiratory pressure 175
Latissimus dorsi 355 Mayo Anesthesia Safety in Kids Study
Left ventricle impairs ventricular filling 163, 165
102 Mayo Clinic-Olmstead County Studies
Left ventricular 162
dysfunction 40 Mean arterial pressure 262
failure 40 Mechanical ventilation 173, 178fc,
Leukocytes 203 181fc, 383
Leukomethylene blue 363 stages of 174
Leukotrienes 368 Medication
Ligamental injuries, multitudes of 203 dispensation of 16
Light weight portable hyperbaric errors, analysis of 13
chambers 320 Medium chain triglyceride 128
Light-headedness 310 Melatonin 160
Index 405
Memory Multicenter randomized controlled trial

disturbance 259 282
failure of 12 Muscle
Mental abdominal 24
hazards 147, 150 mass 24
health 378 exaggerated loss of 28
status 372 relaxants 228
Meperidine 76 weakness 58, 173
Metabolic abnormalities 117, 183 Musculoskeletal system 28
Metabolic disturbance, core of 70 Musculoskeletal tissues 209
Metformin 231 Myasthenia gravis 58
Methemoglobin 364, 366 Mycobacterium tuberculosis 136
formation of 364 Mydriasis 372
levels of 364 Myocardial infarction 29, 215, 216, 226,
Methemoglobinemia 364 378
treatment of 363, 365 Myocardial injury 216, 385, 386
Methylene blue 363, 364, 366, 367, after noncardiac surgery 216
370, 372, 373 Myocardial oxygen 215, 366
adverse effects 371 Myocardial potassium adenosine
contraindications 372 triphosphate 231
current status of 363 Myoclonus 372
historical background 363 Myoglobin 314
mechanism of action 364 Myosin, dephosphorylation of 367
on anesthetics, effect of 365 Myotonic dystrophy 58
physiochemical properties 363
Michigan Health System 15
Micronutrients 123, 126
N
deficiency of 122 Naruke tubeTM (Koken medicals) 300
Midazolam 151, 160 Nasal bleeding, profuse 281
Miglitol 231 Nasal obstruction, severe 281
Military antishock trousers, use of 107 Nasal prongs 280
Milrinone 261 Nasopharynx 340
Minerals 30 National Accreditation Board for
Mini nutritional assessment 116 Hospitals and Healthcare
Minimum alveolar concentration 160, Providers 330, 331t
267 National Audit Project 277
Mitochondria, number of 314 National Council of Radiation
Mobile 138 Protection and Measurement 148
devices 135 National Glycohemoglobin
health imaging 135 Standardization Program 227
information technology National Institute for Health and
applications in hospital Clinical Evidence Guidelines 196
scenario 134 National Institute for Health Care
phone 134 Excellence 206
Modern double-lumen tubes 297 National Surgical Quality Improvement
Monge disease 308 Program 219, 244
Monitoring nutritional therapy 126b Nausea 76, 391
Mood 24 Neostigmine 55, 382
Morphine 168, 389 Nephropathy, contrast-induced 273
Mucociliary clearance function 279 Nervous system 27
Neural development, timeline of 158f risk screening 116

Neurological disturbances 36 therapy 115
Neuromuscular abnormalities 182 Nutritional status, assessment of 116
Neuromuscular blockade 58, 60
Neuromuscular blocking
agent 55, 56, 63
O
drugs, new reversal agents for 63t Obese
Neuromuscular monitoring 382, 383 parturient 70, 72, 79
technique 382 issues and management of 68
Neuroradiological procedures 273t Obesity 68, 69, 73, 74t, 79, 80, 246
Neurotoxic substance 370 in pregnancy 73fc
Neurovascular abnormalities, types of pathophysiology of 70
256 morbid 57
Neurovascular lesions 274 Obstetric management 42
Nicotinamide adenine 364 antihypertensive therapy 43
route of delivery 43
dinucleotide 370
timing of delivery 42
phosphate 363
Obstructive coronary artery disease 216
Nicotine 390
Obstructive sleep apnea 71, 72t, 74
Nifedipine 44, 322-324
incidence of 88
Nimodipine 261 Occupational health hazards 154
Nitric oxide 322, 364 Omega 3 fatty acids 122
synthase 364 Operating room 153, 328, 332, 345, 347
Nitrogen 99 biomedical waste management 345
Nitroglycerine 44 cleaning 345
Nitrous oxide 76, 158, 160 complex design 329
N-methyl-D-aspartate 157, 158, 160, 391 disinfection 345
Noise effects 155 Operation theater 145, 149
Noncardiac surgery 215, 386 Operative delivery 47
Noncatecholamine 363 Ophthalmic manifestations 41
Nonintradiskal platelet-rich plasma Opioids 15, 93, 158, 228
injections 208 anesthetic techniques 228
Non-invasive ventilation 184, 280 intravenous 47
use of 184 parenteral 76
Non-protein energy 128 Optimal pain management 390
Nonsteroidal anti-inflammatory drugs Oral glucose tolerance test 227
205, 249, 392 Oral hypoglycemic agent 231, 231t
Normoglycemia 230 Oral nifedipine 44
North American Spine Society 208 Orthotopic liver transplantation 369
Osmolarity 119
Nosocomial infections, spread of 137
Osteoarthritis knee 203, 205, 206
Numerical rating scale 207
Outpatient arthroplasty risk assessment
Numerous venous channels, presence
247
of 111 Oxidation 314
Nursing delirium screening scale 90 Oxygen 76, 321
NUTRIC score 127 arterial pressure of 309
Nutrients, delivery of 126 delivery 289
Nutrition 24 flow 280
in intensive care unit 115 hemoglobin
monitoring 125 affinity 314
requirements 115 dissociation curve 314
Index 407
partial pressure of 74, 104 Plasma 60

standard 282 Platelet derived growth factor 204
supplemental 322 Platelet-rich plasma 203-205, 209, 210
Oxygenation 176, 277 administration of 203
adequate 175 clinical
evidence of 205, 206
studies of 207
P current use of 209
Pain proposed mechanism of 204
clinics 145 role of 206
intensity 208 studies, limitations for 205
reassessment of 390 types of 204
Pancreatitis, acute 125 Pleural effusion 182
Papworth bivent tube 303 Pneumonia 58, 182, 282
Paracetamol 250 ventilator-associated 120, 173
Paradoxical air embolism 100 Polysomnography 72
Parenteral nutrition 115, 121 Polyurethane 297
complications of 122b Polyvinyl alcohol 272
components of 121 Poor pregnancy outcomes 147, 150
Parkinson’s disease 87 Poor ventilatory response 314
Particulate air, high-efficiency 332, 347 PortexTM (Smith medicals) right-sided
Patent foramen ovale 101, 316 double-lumen tubes 299, 299f
Peak plasma concentrations 28 Positive end-expiratory pressure 107,
Pectoral nerve, lateral 354-356 175, 181, 383
Pediatric Anesthesia 157, 288 Positive pressure ventilation 80, 100
and Neurodevelopment Assessment Positron emission tomography 148
Study 163, 164 Postanesthesia care unit delirium 86
Percutaneous coronary intervention 215 Postembolization angiography 272f
Perfusion 101 Posterior cord 355, 356
Perioperative glycemic control 230 Postextubation stridor, treatment of 185
Perioperative myocardial injury, Postinduction hemodynamics 365
pathophysiology of 217fc Postoperative cardiac
Perioperative Quality Initiative 385 complications 215
Consensus-building Conference 385 computed tomography angiography
Peripheral capillary oxygen saturation 217
50 Postoperative cognitive dysfunction 28
Peripheral vascular disease 87 chances of 95
Peritoneal desufflation 108 Postoperative delirium 85
Pethidine 76 cognitive outcome of 95
Pharmacological prophylaxis 323 development of 87, 87t
Pharyngeal dead space, washout of 279 pathophysiology of 86
Phenotype method 23 prediction of 91
Phenylephrine 261 prevention of 93
Phosphate treatment of 93
levels 126 workup for 89fc
supplements 123 Postoperative myocardial injury 215,
Phosphodiesterase-5 inhibitors 322 216
Physical hazards 146, 147 causes and management 215
Pioglitazones 231 Postoperative pulmonary complications
Placenta, delivery of 42 380, 381
Preanesthetic evaluation 46 Pulmonary edema 36

Preanesthetic preparation 267 risk of 45
Precordial Doppler ultrasound 105 Pulmonary embolism 101
Predicted left main stem bronchus 301 Pulmonary failure 124
diameter 301 Pulmonary function, adequate 175
Pre-eclampsia 34-36, 39, 72 Pulmonary hypertension 75, 323, 373
anesthetic management of 46 development of 314
de novo 35 Pulmonary vasodilator, production of
late onset 38 314
long-term implications of 42 Pulse oximetry 106, 317
management of 34 Pyramidal rigidity 372
oncidence of 37 Pyridostigmine 55
pathogenesis of 37
prophylaxis of 38
risk factors for 39, 39t
Q
signs of 35 QT prolongation 260
symptoms of 35
Pre-existing respiratory infection 316
Pregnancy 69 R
and obesity 73 Radial arterial cannulation 49
normal 74t Radiant heating 198
thromboembolism in 73 Radiation exposure 146, 148
Pre-high efficiency particulate air filters Radio intervention 271
329 Randomized controlled trial 178, 209
Prematurity 161 Rapid ascent profiles 315
Preoperative evaluation and anesthetic Rapid sequence induction/intubation
plan 262 286
Preoxygenation Rapid shallow breathing index 177
adequate 74 Reactive airway disease 319
and apneic oxygenation during
Recent nasal trauma or surgery 281
intubation 284
Receptor agonists 391
Pressure support ventilation 177
Receptor antagonists 391
Prevertebral fascia 360
Red blood cell 92, 102, 364
Progesterone 312
Refeeding syndrome 122, 122b
Proinflammatory mediators 70
Reflective blanket 199
Prolonged weaning failure,
Reflective clothing 199
management of 183
Regional anesthesia 47, 164, 190, 248
Prophylactic aspirin therapy 38
Propofol 158, 160, 193, 228, 265, 267 considerations 48
Proportional assist ventilation 179 Remifentanil 168
Prostacyclin 37 toxicity of 167
Prostatectomy 100 Renal dysfunction 36, 60
Proteinuria 35 Renal failure 36, 124
Pseudomonas aeruginosa 332 Renal function 9
Psychoactive medicines 94 Renal replacement therapy, continuous
Psychosis 91 125
Pulmonary air 100 Renin-angiotensin-aldosterone 316
Pulmonary arterial pressure 313 Reported Edmonton Frail Scale 24
Pulmonary artery catheter 105 Respiration 182
Pulmonary catheters 50 Respiratory depression 76, 79
Index 409
Respiratory distress 287 Sedation 357

clinical signs of 281 risk of 76
Respiratory failure 58, 283 Seizure
Respiratory intermediate intensive care lowering of 391
units 184 prophylaxis 45
Respiratory manifestations 40 Selective serotonin reuptake inhibitor
Respiratory muscle therapy 372
reserve 176 Sensory motor block 77
strength 176 Sepsis 122, 124, 368
Respiratory pathology, absence of 182 Sequential organ failure assessment 127
Respiratory rate 175 Serotonin 157
Respiratory symptoms 36 receptor agonists 391
Respiratory system 27, 73, 79, 261 toxicity 372
Resuscitation signs of 372
algorithms 134 symptoms of 372
cardiopulmonary 109, 134 Serum creatinine levels 36
rooms 145 Severe pre-eclampsia 36t, 40-42, 46,
Reversal agent sugammadex 228 48, 49
Revised cardiac risk index 219, 221 systemic manifestations of 40
Richmond agitation-sedation scale 89, Sevoflurane 158, 167
90f subclinical 160
Robertshaw design 297 SheridanTM (teleflex) 299
Robertshaw double-lumen tube, Shock 364
left-sided 297f anaphylactic 368
Robertshaw tube 296, 305 hypovolemic 369
Robot-assisted medication preparation septic 368
16 vasodilatory 366, 368
Robotic preparation 16 vasoplegic 366
Rocuronium 13 worsening 117
induced neuromuscular blockade Short nutritional assessment
58 questionnaire 116
potency of 57 Shoulder
Roland-Morris disability questionnaire dystocia 72, 73
208 innervation 354f
Rosiglitazones 231 painful procedures 353
Rotator cuff repair 357 regional anesthesia 353
Royal College of Anaesthetists 277 surgery, regional blocks for 353
RüschTM left-sided double-lumen tubes SilbronchoTM 299
298, 298f, 300 Simple ventilatory parameters 176
Simplified weaning index 176
Simulation techniques 134
S Single shot spinal anesthesia 48
Sacroiliac joint 208 Sinusitis 173
injection 208 Sitagliptin 231, 232
Safety critical patient areas 139, 140 Sleep deprivation 94
Salmeterol 324 Smart magnetic resonance imaging 134
Sarcopenia 24, 28 SmartCareTM 180
Scapula, spine of 356 Smartphone
Schizophrenia, psychotic illnesses like and medical equipment 139
91 application 135
cost-effective ventilator 136 Stress

guidelines regarding safe use of 140 ambience-related 147, 151
in anesthesia 133 and burnout 147, 150
Sniff position 79 operative 382
Social networking sites, variety of 135 Stroke 25
Society for Ambulatory Anesthesia 230, acute 273
234 history of 87
Society for Healthcare Epidemiology of volume variation 219
America 333 Stromal vascular fraction 208
summary of 334t Subarachnoid hemorrhage 256, 273
Society of Critical Care Medicine 116 diffuse deposits of 260
Society of Thoracic Surgeons 237 severity of 259
Sodium systemic manifestations of 260
channel blockers 391 Subomohyoid 358
nitroprusside 44 Subscapular fossa 356
Substance abuse 147, 151, 257, 390
Soldiers deployed for counter-
Sugammadex 55, 58, 60, 61, 63, 382
insurgency operations 311
administration of 59
Soluble endoglin 38
dose 56, 56t
Soluble guanylyl cyclase 364
reversal 63
inhibition of 364
rocuronium complex 60
Somnolence 79
use of 56
Sparing phrenic nerve 353
Sulfonylureas 231
Spetzler-Martin Grade of Arteriovenous Superficial cervical block 357
Malformation 270t Superior labrum
Spetzler-Martin grading system 269 anterior 357
Spinal anesthesia 48, 77, 163 posterior 357
block neuronal impulses 193 Supraclavicular area 360
study 163 Supraclavicular nerves 357, 360
Spinal fusion 100 Suprascapular fossa 358
Spinoglenoid notch 356 Suprascapular nerve 354-356
Spontaneous breathing block 358
pattern of 176 Suprascapular notch 354, 356
trial 173, 177, 178fc, 181 Supraspinous fossa 356
Spontaneous intermittent mandatory Surgical clipping, anesthetic
ventilation 177 management of 262
Spontaneous ventilation 287 Surgical site infection 195, 328
Sputum smears 136 causes of 328
Stable metabolic status 175 Swan-Ganz catheter 219
Steam sterilization 345 Synaptogenesis 165
Stenotrophomonas maltophilia 332 Syndrome of inappropriate secretion of
Sterile cockpit rules 138 antidiuretic hormone 261
Sterilization Systemic inflammatory response 102
measures 341 Systemic lupus erythematosus 39
techniques of OR 341 Systemic vascular resistance 40, 366
Steroidal nondepolarizing
neuromuscular agents 55
Steroids, intra-articular injection of 205
T
Stethoscopes 106 Tachycardia 221, 317, 372, 386
Strain limited human attention span 141 Tachypnea 317, 372
Index 411
Testosterone 30 Tumor necrosis factor 217, 227

The 1800 rule 233 alpha 116
Thermal dysregulation, causes of 192
Thermal insulation mechanisms 199
Thermoluminescent dosimeter 267
U
Thermoregulation 190, 191 Ultrasonography 303
intraoperative 190 Ultrasound
Thiazolidinediones 231 limitations of 319
Thiopentone 228, 265 lung comets, presence of 319
Third nerve palsy 259 Univent tube 294f
Thrombocytopenia 36, 41 Upper airway 173
Thromboelastography 49 Upper extremity 359
Thromboembolism 73 distal part of 357
Thrombus 215 Upper gastrointestinal bleeding,
Tidal volume 175 refractory 117
Tissue 314 Urea 126
cytochrome oxidase 314 Urine dipstick 35
Total hip arthroplasty 244 Uteroplacental blood flow 41
Total intravenous anesthesia 134
advantage of 88 V
Total joint arthroplasty 244, 245, 252
program 245 Vaginal rings 61
Total knee Variable rate insulin infusion 232
arthroplasty 244 Vascular air embolism 99, 112
replacement 205 Vascular catheters 107
Total parenteral nutrition 237 Vascular endothelial growth factor 204
Tracheostomy 183 Vasoplegia 366, 367
Traditional nerve blocks 353 Vasoplegic syndrome 366, 367
Tramadol 391 Vasopressor 49, 364
advantage of 391 Vasospasm, management of 261b
diclofenac, fixed-dose combination Venous air embolism 103
of 392 Venous thromboembolism 81, 250
pharmacodynamic activity of 392 Ventilation 312
Tranexamic acid 249 Ventricular pressures 218
Transcranial Doppler ultrasound 106 Ventricular septal defects 316
Transesophageal echocardiography 51, Venturi mask 277
105, 219, 316 Video laryngoscope 134
Transforming growth factor-beta 204 Visual aid 92
Transnasal humidified rapid- Visual analog scale 207, 389
insufflation ventilatory exchange Visual disturbances 36
285 Visual impairment 94
Transthoracic echocardiography 377 Vital capacity 175
Transverse abdominis plane block 80 Vitamin 30, 121
Transverse humeral ligament 355 C 40
Trauma 124, 145 D deficiency 38
Tremor 371, 372 D supplementation 123
Tricyclic antidepressants 87 Viva-sight double-lumen tubes 304f
Triglycerides 126 Volatile anesthetic gases 147
Trophoblastic invasion, failure of 37 Vomiting 76, 371
W protocol 180
readiness, assessment of 175
Wander app 134 ventilator modes for 178
Warming, methods of 198
White blood cell 195
Waste gas exposure 146, 147, 154
Water distribution system 332 White coat hypertension 35
Weakness 310 World Federation of Neurological
Weaning 184 Surgeons Grading for
anticipation of 174 Intracranial Aneurysm
conventional methods of 177 259t
different conventional modes of 178 World Federation of Neurosurgeons
failure 180 Scale 259
fluid management of 185
World Health Organization 22, 69, 136,
parameters
combination of 175 146
common 176t Wound infection 73

Yearbook Anaesthesiology

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Yearbook Anaesthesiology

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Yearbook of

2. B Radhakrishnan MD MPhil FICA

3. Jayashree Sood MD FFARCS PGDHHM FICA

4. Baljit Singh MD FICA

Anjan Trikha MD FICA

Indian College of Anaesthesiologists

JAYPEE BROTHERS MEDICAL PUBLISHERS

Devalina Goswami MD Kumar G Belani MS FACA FAAP

Kapil Dev Soni MD Maj Gen Rashmi Datta VSM MD MG (Med)

Neetu Jain MD DNB Purnima Dhar MD

Sanjay Sharma MD FANZCA GCCS MHSM Susheela Taxak DA MD DNBE

Surinder Mohan Sharma MD DMICAc FICA

Baljit Singh MD FICA

neurovascular procedures have been covered along with complications

2. Perioperative Care of the Frail Elderly:

3. Pregnancy-induced Hypertension: An Update .....................34

• Systemic Manifestations of Severe Pre-eclampsia 40

4. Sugammadex and Beyond......................................................55

5. Issues and Management of Obese Parturient.......................68

6. Postoperative Delirium: A Bane of Daycare Surgery............85

7. Gas Embolism: An Update......................................................99

9. Smartphones in Anesthesia: Game Changers or

10. Health Hazards for an Anesthesiologist:

11. Effect of Anesthesia on the Developing Brain:

12. Weaning from Mechanical Ventilation .................................173

13. Intraoperative Thermoregulation .........................................190

14. Platelet-rich Plasma for Management of Chronic

• Current Use of Platelet-rich Plasma in Musculoskeletal

15. Postoperative Myocardial Injury: Causes and

16. Management of Hyperglycemia in the

17. Challenges and Issues in Daycare Arthroplasty ................244

• Patient Education and Social Optimization 247

18. Anesthesia for Neurovascular Procedures ........................256

19. High-flow Nasal Oxygenation: A Fad? ................................277

20. Double-lumen Endotracheal Tubes: From History to

22. Infection Prevention in the Operating Room.......................328

23. Regional Blocks for Shoulder Surgery:

24. Current Status of Methylene Blue in Anesthesia and

25. Journal Scan ..........................................................................377

CLASSIFICATION OF ERRORS BASED ON

adverse outcomes actually follow only in a small proportion. The larger

IS THE TERM “ERROR” THE MOST

As per the Swiss cheese theory, multiple complex factors contribute

ROLE OF HUMAN FACTORS IN GENESIS OF ERROR

“HIGHLY COMPLEX, TIGHTLY COUPLED”

involved in ensuring a good outcome, but also the unpredictable

CHANGING APPROACH TO ERROR

Recognition that errors are often based on complex interactions of human

CAUSATION OF ERRORS ALSO MIRED IN MYTHS

MEDICATION ERRORS IN THE HOSPITAL

The other high-risk population is young children, as drug prescriptions

CLASSIFICATION OF MEDICAL ERRORS

MEDICATION ERRORS SPECIFIC TO THE

Table 1: Incidence of medication errors in key studies.

contributions of 4 and 2% respectively were attributable to administration

Table 2: Classification of drug errors.

litigation concerns in caregiver as well as damaged public perception are

ERROR REDUCTION AND PREVENTION—

medical records, large labels highlighting high-risk drugs, and similar

• Robot-assisted medication preparation: With accelerated progress of

anesthesiologists and their institutions. It appears that there continues to be

7. Department of Health. An organization with a memory: Report of an expert

51. Glavin RJ. Drug errors: consequences, mechanisms, and avoidance. Br J